起搏通道电生理特性研究
|
摘要
细胞是生命活动的基本单位。一切有机体都是由细胞构成的，它是有机体生长与发育的基础，也是遗传的基本单位，因此，没有细胞就没有完整的生命。所有的动物细胞都由一层薄膜所包围，这就是细胞膜(plasma membrane)，细胞膜的作用是保持细胞内物质成分的稳定。但是，细胞膜并不是完全封闭的，细胞需要跟外界交换物质和能量，细胞膜上的离子通道就是具备这种功能的蛋白质，离子通道可以分为配体门控通道、电压门控通道、胞内信号门控通道和机械敏感通道四种类型。
超极化激活的环核苷酸门控(hyperpolarization-activated cyclic nucleotide-gated，HCN)通道(起搏通道)是一种能被电压和环磷酸腺苷(cAMP)调控的、无选择性阳离子通道，它介导的电流是Ih。Ih广泛的参与了对一系列生理活动的调控，包括心脏和神经元节律，某些可兴奋细胞的静息电位，神经信号的传递以及信号在树突中的整合等。Ih受自主神经系统和神经内分泌系统的调节以及某些病理状态的影响，Ih异常会导致心脏及精神方面的多种疾病。因此，研究Ih有重要的生理学意义。
本文着重应用电生理膜片钳、全细胞钙成像、神经疼痛模型等技术对HCN通道的调控机制、在神经疼痛中的作用及其药理学特性进行了研究和探讨。
本文主要研究结果和结论如下：
（1）PKA信号通路在调控HCN通道活性中的作用。PKA广泛分布于细胞体内，参与了对一些列重要生理活动的调控。然而，抑制PKA对HCN通道活性有何影响，目前仍不清楚。为了弄清这一问题，我们选择了PKA的选择性抑制剂KT5720。在新鲜分离的大鼠DRG神经元上，综合运用全细胞电压钳、电流钳、单通道记录以及钙成像技术。揭示了PKA信号通路在调控HCN通道活性中发挥了极为重要的作用，KT5720抑制HCN通道活性，使其电流密度减小，半数开放电压向超极化方向移动，并使其通道开放的时间常数增加。此外，KT5720抑制PKA使DRG神经元上的动作电位减小、胞内Ca2+浓度降低，从而抑制DRG神经元的兴奋性。
（2）HCN通道调控神经疼痛。神经疼痛通常由神经损伤引发，因其具有发病率高、难治愈等特点，已成为当今医学界亟待解决的主要问题之一。另一方面，DRG神经元是感觉传入的第一级神经元，在疼痛信号的传导过程中发挥着不可或缺的重要作用。因此，我们选择DRG神经元为研究对象，利用大鼠幸免神经损伤模型。综合运用多种电生理膜片钳实验方法，研究和探讨了HCN通道在调控神经疼痛中的机制，揭示了HCN通道是触发和维持神经疼痛的关键因素。在幸免神经损伤诱导的疼痛状态下，DRG神经元上的HCN通道活性显著增加，异位放电频率变快，且DRG形态发生变化。因此，HCN通道是有效治疗神经疼痛的潜在靶点。
（3）麻黄碱对HCN通道的影响。麻黄碱作为一种肾上腺受体激动药，具有加强心收缩力、增加心输出量、加快心率、升高血压等作用。为了弄清麻黄碱的这些作用是否是通过HCN通道来实现的以及它对HCN通道电流有什么影响。我们采用传统的全细胞膜片钳实验方法，在新生的大鼠海马神经元和HEK细胞上记录到HCN通道电流Ih。实验结果显示，麻黄碱对Ih有抑制作用。经分析，我们认为HCN通道可能具备某种反馈及保护功能，即当血压和心率上升时，HCN通道能部分阻滞这种上升趋势，从而保护机体健康和生命安全。
Cell is the basic unit of life. All organisms composed of cells, it is the basis oforganism growth and development. It's also the basic unit of heredity. Overall, cell is thefundamental element of life. All animal cells are surrounded by a layer of film, which iscell membrane. It serves as a fence to keep intracellular materious and circumstancesstable. However, cell membrane is not absolutly sealed. Cells need to exchange materialsand energies with outside. Ion channels located in cell membrane perform this function.Ion channels can be classified into four types: ligand-gated channels, voltage-gatedchannels, intracellular signal-gated channels and mechanical sensitive channels.
hyperpolarization-activated cyclic nucleotide-gated channel (pacemaker channel) is anon-selective cation channel which can be regulated by both voltage and cyclic adenosinemonophosphate (cAMP), the associated underlying current is Ih, Ihinvolved in regulatinga series of physiological processes, such as controling pacemaker activities in both heartand neurons, governing the resting membrane potential of some excitable cells, transferingnerve signals and signals in dendritic integration. Ihis regulated by the autonomic nervoussystem and neuroendocrine system and is affected by some pathological conditions. Itsdysfunction may induce many heart and mental diseases. Therefore, study Ihhas importantphysiological significances.
At this present study, by using electrophysiological patch-clamp recording, whole cellCa2+imaging as well as a rat spared-nerve injury model, its regulation mechanisms, itsrole in neuropathic pain and its pharmacological properties are investigated.
The main results are as follows:
(1) The role of PKA signal pathway on regulating HCN channel activity. ProteinKinase A (PKA) is widely expressed in almost all types of cells, it involved in controllingand regulating a serial of pivotal physiological processes, while the effect of PKAinhibition on HCN channel activity is yet to be decided. To address this issue, we chosedKT5720, a selective PKA inhibitor. With using whole-cell voltage clamp, current clamp,single channel patch-clamp recording as well as Ca2+imaging, on freshly isolated DRGneurons. Our investigations revealed that PKA signal pathway plays a crucial role on regulating HCN channel activity, KT5720attenuated HCN channel activity. In presence of3μM KT5720, HCN channel currents density decreased. Its V1/2shifted tohyperpolarization direction, and the channel activation time constant significantlyincreased. Moreover, PKA inhibition with KT5720attenuated the action potentials (APs)and decreased intracellular Ca2+level, which therefore dampened DRG neuronsexcitability.
(2) The role of HCN channel on regulating neuropathic pain. Neuropathic pain wascharacterized with high incidence and refractory, which often associated with nerve injury.It's a major medical problem yet to be resolved. On the other hand, DRG neuron is theprimary sensory afferent, it's essential for pain signal transportation. Hence, we choseDRG neuron as our study subject, on spared-nerve injury model, with using multipleelectrophysiological patch-clamp recording methods. We studied the underlyingmechanisms of HCN channel regulating neuropathic pain, unveiled that HCN channel is akey mediator on triggering and maintaining neuropathic pain. Under spared nerve injuryinduced pain condition, HCN channel activity in DRG neuron significantly increased, theectopic discharge frequency potentiated, and DRG morphology changed. Therefore, HCNchannel represents a novel potential target for the treatment of this disease.
(3) The impact of ephedrine on HCN channel activity. Ephedrine is an adrenalagonist, which has the functions of strengthening heart contraction, enhancing cardiacoutput, potentiating heart rate and improving blood pressure as well. To investigate ifHCN channel involved in these regulations, we carried out experiments with conventionalwhole-cell patch-clamp recording method. We obtained HCN channel current Ihonneonatal rat hippocampal neurons and HEK cells. Our experimental results indicated thatIhattenuated by ephedrine. The likelihood mechanism is that HCN channel has somefeedback functions. When blood pressure or heart rate increases abnormally, HCN channelbeing able to partly block these momentums, and therefor maintains organisms' health andlife safety.
超极化激活的环核苷酸门控(hyperpolarization-activated cyclic nucleotide-gated，HCN)通道(起搏通道)是一种能被电压和环磷酸腺苷(cAMP)调控的、无选择性阳离子通道，它介导的电流是Ih。Ih广泛的参与了对一系列生理活动的调控，包括心脏和神经元节律，某些可兴奋细胞的静息电位，神经信号的传递以及信号在树突中的整合等。Ih受自主神经系统和神经内分泌系统的调节以及某些病理状态的影响，Ih异常会导致心脏及精神方面的多种疾病。因此，研究Ih有重要的生理学意义。
本文着重应用电生理膜片钳、全细胞钙成像、神经疼痛模型等技术对HCN通道的调控机制、在神经疼痛中的作用及其药理学特性进行了研究和探讨。
本文主要研究结果和结论如下：
（1）PKA信号通路在调控HCN通道活性中的作用。PKA广泛分布于细胞体内，参与了对一些列重要生理活动的调控。然而，抑制PKA对HCN通道活性有何影响，目前仍不清楚。为了弄清这一问题，我们选择了PKA的选择性抑制剂KT5720。在新鲜分离的大鼠DRG神经元上，综合运用全细胞电压钳、电流钳、单通道记录以及钙成像技术。揭示了PKA信号通路在调控HCN通道活性中发挥了极为重要的作用，KT5720抑制HCN通道活性，使其电流密度减小，半数开放电压向超极化方向移动，并使其通道开放的时间常数增加。此外，KT5720抑制PKA使DRG神经元上的动作电位减小、胞内Ca2+浓度降低，从而抑制DRG神经元的兴奋性。
（2）HCN通道调控神经疼痛。神经疼痛通常由神经损伤引发，因其具有发病率高、难治愈等特点，已成为当今医学界亟待解决的主要问题之一。另一方面，DRG神经元是感觉传入的第一级神经元，在疼痛信号的传导过程中发挥着不可或缺的重要作用。因此，我们选择DRG神经元为研究对象，利用大鼠幸免神经损伤模型。综合运用多种电生理膜片钳实验方法，研究和探讨了HCN通道在调控神经疼痛中的机制，揭示了HCN通道是触发和维持神经疼痛的关键因素。在幸免神经损伤诱导的疼痛状态下，DRG神经元上的HCN通道活性显著增加，异位放电频率变快，且DRG形态发生变化。因此，HCN通道是有效治疗神经疼痛的潜在靶点。
（3）麻黄碱对HCN通道的影响。麻黄碱作为一种肾上腺受体激动药，具有加强心收缩力、增加心输出量、加快心率、升高血压等作用。为了弄清麻黄碱的这些作用是否是通过HCN通道来实现的以及它对HCN通道电流有什么影响。我们采用传统的全细胞膜片钳实验方法，在新生的大鼠海马神经元和HEK细胞上记录到HCN通道电流Ih。实验结果显示，麻黄碱对Ih有抑制作用。经分析，我们认为HCN通道可能具备某种反馈及保护功能，即当血压和心率上升时，HCN通道能部分阻滞这种上升趋势，从而保护机体健康和生命安全。
Cell is the basic unit of life. All organisms composed of cells, it is the basis oforganism growth and development. It's also the basic unit of heredity. Overall, cell is thefundamental element of life. All animal cells are surrounded by a layer of film, which iscell membrane. It serves as a fence to keep intracellular materious and circumstancesstable. However, cell membrane is not absolutly sealed. Cells need to exchange materialsand energies with outside. Ion channels located in cell membrane perform this function.Ion channels can be classified into four types: ligand-gated channels, voltage-gatedchannels, intracellular signal-gated channels and mechanical sensitive channels.
hyperpolarization-activated cyclic nucleotide-gated channel (pacemaker channel) is anon-selective cation channel which can be regulated by both voltage and cyclic adenosinemonophosphate (cAMP), the associated underlying current is Ih, Ihinvolved in regulatinga series of physiological processes, such as controling pacemaker activities in both heartand neurons, governing the resting membrane potential of some excitable cells, transferingnerve signals and signals in dendritic integration. Ihis regulated by the autonomic nervoussystem and neuroendocrine system and is affected by some pathological conditions. Itsdysfunction may induce many heart and mental diseases. Therefore, study Ihhas importantphysiological significances.
At this present study, by using electrophysiological patch-clamp recording, whole cellCa2+imaging as well as a rat spared-nerve injury model, its regulation mechanisms, itsrole in neuropathic pain and its pharmacological properties are investigated.
The main results are as follows:
(1) The role of PKA signal pathway on regulating HCN channel activity. ProteinKinase A (PKA) is widely expressed in almost all types of cells, it involved in controllingand regulating a serial of pivotal physiological processes, while the effect of PKAinhibition on HCN channel activity is yet to be decided. To address this issue, we chosedKT5720, a selective PKA inhibitor. With using whole-cell voltage clamp, current clamp,single channel patch-clamp recording as well as Ca2+imaging, on freshly isolated DRGneurons. Our investigations revealed that PKA signal pathway plays a crucial role on regulating HCN channel activity, KT5720attenuated HCN channel activity. In presence of3μM KT5720, HCN channel currents density decreased. Its V1/2shifted tohyperpolarization direction, and the channel activation time constant significantlyincreased. Moreover, PKA inhibition with KT5720attenuated the action potentials (APs)and decreased intracellular Ca2+level, which therefore dampened DRG neuronsexcitability.
(2) The role of HCN channel on regulating neuropathic pain. Neuropathic pain wascharacterized with high incidence and refractory, which often associated with nerve injury.It's a major medical problem yet to be resolved. On the other hand, DRG neuron is theprimary sensory afferent, it's essential for pain signal transportation. Hence, we choseDRG neuron as our study subject, on spared-nerve injury model, with using multipleelectrophysiological patch-clamp recording methods. We studied the underlyingmechanisms of HCN channel regulating neuropathic pain, unveiled that HCN channel is akey mediator on triggering and maintaining neuropathic pain. Under spared nerve injuryinduced pain condition, HCN channel activity in DRG neuron significantly increased, theectopic discharge frequency potentiated, and DRG morphology changed. Therefore, HCNchannel represents a novel potential target for the treatment of this disease.
(3) The impact of ephedrine on HCN channel activity. Ephedrine is an adrenalagonist, which has the functions of strengthening heart contraction, enhancing cardiacoutput, potentiating heart rate and improving blood pressure as well. To investigate ifHCN channel involved in these regulations, we carried out experiments with conventionalwhole-cell patch-clamp recording method. We obtained HCN channel current Ihonneonatal rat hippocampal neurons and HEK cells. Our experimental results indicated thatIhattenuated by ephedrine. The likelihood mechanism is that HCN channel has somefeedback functions. When blood pressure or heart rate increases abnormally, HCN channelbeing able to partly block these momentums, and therefor maintains organisms' health andlife safety.
引文
[1] Jiang, Y., Pico, A., Cadene, M., et al. Structure of the RCK domain from the E. coli K+channel and demonstration of its presence in the human BK channel. Neuron.2001.29(3):593-601.
[2] Valiyaveetil, F.I., Zhou, Y., and Mackinnon, R. Lipids in the structure, folding, andfunction of the KcsA K+channel. Biochemistry.2002.41(35):10771-10777.
[3] Long, S.B., Campbell, E.B., and Mackinnon, R. Crystal structure of a mammalianvoltage-dependent Shaker family K+channel. Science.2005.309(5736):897-903.
[4] Jiang, Y., Lee, A., Chen, J., et al. Crystal structure and mechanism of a calcium-gatedpotassium channel. Nature.2002.417(6888):515-522.
[5] Lee, S.Y., Lee, A., Chen, J., et al. Structure of the KvAP voltage-dependent K+channel and its dependence on the lipid membrane. Proc Natl Acad Sci U S A.2005.102(43):15441-15446.
[6] Nishida, M., Cadene, M., Chait, B.T., et al. Crystal structure of a Kir3.1-prokaryoticKir channel chimera. Embo J.2007.26(17):4005-4015.
[7] Jiang, Y., Lee, A., Chen, J., et al. X-ray structure of a voltage-dependent K+channel.Nature.2003.423(6935):33-41.
[8] Gulbis, J.M., Mann, S., and Mackinnon, R. Structure of a voltage-dependent K+channel beta subunit. Cell.1999.97(7):943-952.
[9] Gulbis, J.M., Zhou, M., Mann, S., et al. Structure of the cytoplasmic beta subunit-T1assembly of voltage-dependent K+channels. Science.2000.289(5476):123-127.
[10] Veizerova, L., Svetlik, J., and Kettmann, V. Voltage gated calcium channels: structure,characteristics and terminology. Ceska Slov Farm.2007.56(4):178-182.
[11] Bezanilla, F. The voltage-sensor structure in a voltage-gated channel. Trends BiochemSci.2005.30(4):166-168.
[12] Giorgi, C., Romagnoli, A., Pinton, P., et al. Ca2+signaling, mitochondria and celldeath. Curr Mol Med.2008.8(2):119-130.
[13] Belkacemi, L., Bedard, I., Simoneau, L., et al. Calcium channels, transporters andexchangers in placenta: a review. Cell Calcium.2005.37(1):1-8.
[14] Huc, S., Monteil, A., Bidaud, I., et al. Regulation of T-type calcium channels:Signalling pathways and functional implications. Biochim Biophys Acta.2008.
[15] Khosravani, H. and Zamponi, G.W. Voltage-gated calcium channels and idiopathicgeneralized epilepsies. Physiol Rev.2006.86(3):941-966.
[16] Treinys, R. and Jurevicius, J. L-type Ca2+channels in the heart: structure andregulation. Medicina (Kaunas).2008.44(7):491-499.
[17] Hofmann, F., Lacinova, L., and Klugbauer, N. Voltage-dependent calcium channels:from structure to function. Rev Physiol Biochem Pharmacol.1999.139:33-87.
[18] Haase, H., Pfitzmaier, B., Mcenery, M.W., et al. Expression of Ca(2+) channelsubunits during cardiac ontogeny in mice and rats: identification of fetal alpha(1C)and beta subunit isoforms. J Cell Biochem.2000.76(4):695-703.
[19] Hell, J.W., Westenbroek, R.E., Warner, C., et al. Identification and differentialsubcellular localization of the neuronal class C and class D L-type calcium channelalpha1subunits. J Cell Biol.1993.123(4):949-962.
[20] Baumann, L., Gerstner, A., Zong, X., et al. Functional characterization of the L-typeCa2+channel Cav1.4alpha1from mouse retina. Invest Ophthalmol Vis Sci.2004.45(2):708-713.
[21] Davis, M.J. and Hill, M.A. Signaling mechanisms underlying the vascular myogenicresponse. Physiol Rev.1999.79(2):387-423.
[22] Henquin, J.C. and Meissner, H.P. Significance of ionic fluxes and changes inmembrane potential for stimulus-secretion coupling in pancreatic B-cells.Experientia.1984.40(10):1043-1052.
[23] Frey, N., Mckinsey, T.A., and Olson, E.N. Decoding calcium signals involved incardiac growth and function. Nat Med.2000.6(11):1221-1227.
[24] Quartermain, D. Chronic administration of the Ca(2+) channel blocker amlodipinefacilitates learning and memory in mice. Eur J Pharmacol.2000.399(1):57-63.
[25] Woodside, B.L., Borroni, A.M., Hammonds, M.D., et al. NMDA receptors andvoltage-dependent calcium channels mediate different aspects of acquisition andretention of a spatial memory task. Neurobiol Learn Mem.2004.81(2):105-114.
[26] Bauer, E.P., Schafe, G.E., and Ledoux, J.E. NMDA receptors and L-typevoltage-gated calcium channels contribute to long-term potentiation and differentcomponents of fear memory formation in the lateral amygdala. J Neurosci.2002.22(12):5239-5249.
[27] Fox, A.P., Cahill, A.L., Currie, K.P., et al. N-and P/Q-type Ca2+channels in adrenalchromaffin cells. Acta Physiol (Oxf).2008.192(2):247-261.
[28] Gazulla, J. and Tintore, M.[P/Q-type voltage-dependent calcium channels inneurological disease]. Neurologia.2007.22(8):511-516.
[29] Gazulla, J. and Tintore, M. The P/Q-type voltage-dependent calcium channel: atherapeutic target in spinocerebellar ataxia type6. Acta Neurol Scand.2007.115(5):356-363.
[30] Janssen, L.J. and Kwan, C.Y. ROCs and SOCs: what's in a name? Cell Calcium.2007.41(3):245-247.
[31] Baranauskas, G. Ionic channel function in action potential generation: currentperspective. Mol Neurobiol.2007.35(2):129-150.
[32] Christe, G., Chahine, M., Chevalier, P., et al. Changes in action potentials andintracellular ionic homeostasis in a ventricular cell model related to a persistentsodium current in SCN5A mutations underlying LQT3. Prog Biophys Mol Biol.2008.96(1-3):281-293.
[33] Yamaoka, K., Vogel, S.M., and Seyama, I. Na+channel pharmacology and molecularmechanisms of gating. Curr Pharm Des.2006.12(4):429-442.
[34] Isom, L.L. Sodium channel beta subunits: anything but auxiliary. Neuroscientist.2001.7(1):42-54.
[35] Hanlon, M.R. and Wallace, B.A. Structure and function of voltage-dependent ionchannel regulatory beta subunits. Biochemistry.2002.41(9):2886-2894.
[36] Pfahnl, A.E., Viswanathan, P.C., Weiss, R., et al. A sodium channel pore mutationcausing Brugada syndrome. Heart Rhythm.2007.4(1):46-53.
[37] Goldin, A.L. Mechanisms of sodium channel inactivation. Curr Opin Neurobiol.2003.13(3):284-290.
[38] Blumenthal, K.M. and Seibert, A.L. Voltage-gated sodium channel toxins: poisons,probes, and future promise. Cell Biochem Biophys.2003.38(2):215-238.
[39] Cestele, S. and Catterall, W.A. Molecular mechanisms of neurotoxin action onvoltage-gated sodium channels. Biochimie.2000.82(9-10):883-892.
[40] Endoh, M. A Na+channel agonist: a potential cardiotonic agent with a novelmechanism? Br J Pharmacol.2004.143(6):663-665.
[41] Gonoi, T., Ohizumi, Y., Kobayashi, J., et al. Actions of a polypeptide toxin from themarine snail Conus striatus on voltage-sensitive sodium channels. Mol Pharmacol.1987.32(5):691-698.
[42] Noskov, S.Y. and Roux, B. Ion selectivity in potassium channels. Biophys Chem.2006.124(3):279-291.
[43] Mannhold, R. Structure-activity relationships of K(ATP) channel openers. Curr TopMed Chem.2006.6(10):1031-1047.
[44] Wang, Y., Cheng, J., Tandan, S., et al. Transient-outward K+channel inhibitionfacilitates L-type Ca2+current in heart. J Cardiovasc Electrophysiol.2006.17(3):298-304.
[45] Salkoff, L., Wei, A.D., Baban, B., et al. Potassium channels in C. elegans. WormBook.2005:1-15.
[46] Calloe, K., Cordeiro, J.M., Di Diego, J.M., et al. A transient outward potassiumcurrent activator recapitulates the electrocardiographic manifestations of Brugadasyndrome. Cardiovasc Res.2009.81(4):686-694.
[47] Bai, J., Ren, C., Hao, W., et al. Chemical sympathetic denervation, suppression ofmyocardial transient outward potassium current, and ventricular fibrillation in therat. Can J Physiol Pharmacol.2008.86(10):700-709.
[48] Wagner, M., Goltz, D., Stucke, C., et al. Modulation of the transient outward K+current by inhibition of endothelin-A receptors in normal and hypertrophied rathearts. Pflugers Arch.2007.454(4):595-604.
[49] Belugin, S. and Mifflin, S. Transient voltage-dependent potassium currents arereduced in NTS neurons isolated from renal wrap hypertensive rats. JNeurophysiol.2005.94(6):3849-3859.
[50] Fedida, D. and Hesketh, J.C. Gating of voltage-dependent potassium channels. ProgBiophys Mol Biol.2001.75(3):165-199.
[51] Gardiwal, A., Klein, G., Kraemer, K., et al. Reduced delayed rectifier K+current,altered electrophysiology, and increased ventricular vulnerability in MLP-deficientmice. J Card Fail.2007.13(8):687-693.
[52] Kofuji, P. and Newman, E.A. Potassium buffering in the central nervous system.Neuroscience.2004.129(4):1045-1056.
[53] Tada, Y., Horio, Y., and Kurachi, Y. Inwardly rectifying K+channel in retinal Mullercells: comparison with the KAB-2/Kir4.1channel expressed in HEK293T cells.Jpn J Physiol.1998.48(1):71-80.
[54] Benhassine, N. and Berger, T. Homogeneous distribution of large-conductancecalcium-dependent potassium channels on soma and apical dendrite of ratneocortical layer5pyramidal neurons. Eur J Neurosci.2005.21(4):914-926.
[55] Ghisdal, P. and Morel, N. Cellular target of voltage and calcium-dependent K(+)channel blockers involved in EDHF-mediated responses in rat superior mesentericartery. Br J Pharmacol.2001.134(5):1021-1028.
[56] Cornfield, D.N., Reeve, H.L., Tolarova, S., et al. Oxygen causes fetal pulmonaryvasodilation through activation of a calcium-dependent potassium channel. ProcNatl Acad Sci U S A.1996.93(15):8089-8094.
[57] Mital, S. and Konduri, G.G. Vascular potassium channels mediate oxygen-inducedpulmonary vasodilation in fetal lambs. Biol Neonate.2000.77(1):58-68.
[58] Jentsch, T.J. CLC chloride channels and transporters: from genes to protein structure,pathology and physiology. Crit Rev Biochem Mol Biol.2008.43(1):3-36.
[59] Vandewalle, A. Expression and function of CLC and cystic fibrosis transmembraneconductance regulator chloride channels in renal epithelial tubule cells:pathophysiological implications. Chang Gung Med J.2007.30(1):17-25.
[60] Lotshaw, D.P., Levitan, E.S., and Levitan, I.B. Fine tuning of neuronal electricalactivity: modulation of several ion channels by intracellular messengers in a singleidentified nerve cell. J Exp Biol.1986.124:307-322.
[61] Knauf, P.A. and Mann, N.A. Location of the chloride self-inhibitory site of the humanerythrocyte anion exchange system. Am J Physiol.1986.251(1Pt1): C1-9.
[62] Powell, K.L., Cain, S.M., Ng, C., et al. A Cav3.2T-type calcium channel pointmutation has splice-variant-specific effects on function and segregates with seizureexpression in a polygenic rat model of absence epilepsy. J Neurosci.2009.29(2):371-380.
[63] Saito, Y.A., Strege, P.R., Tester, D.J., et al. Sodium channel mutation in irritablebowel syndrome: evidence for an ion channelopathy. Am J Physiol GastrointestLiver Physiol.2009.296(2): G211-218.
[64] Teng, G.Q., Zhao, X., Lees-Miller, J.P., et al. Homozygous missense N629D hERG(KCNH2) potassium channel mutation causes developmental defects in the rightventricle and its outflow tract and embryonic lethality. Circ Res.2008.103(12):1483-1491.
[65] Noma, A. and Irisawa, H. Membrane currents in the rabbit sinoatrial node cell asstudied by the double microelectrode method. Pflugers Arch.1976.364(1):45-52.
[66] Brown, H.F., Difrancesco, D., and Noble, S.J. How does adrenaline accelerate theheart? Nature.1979.280(5719):235-236.
[67] Halliwell, J.V. and Adams, P.R. Voltage-clamp analysis of muscarinic excitation inhippocampal neurons. Brain Res.1982.250(1):71-92.
[68] Bakondi, G., Por, A., Kovacs, I., et al. Hyperpolarization-activated, cyclicnucleotide-gated, cation non-selective channel subunit expression pattern ofguinea-pig spiral ganglion cells. Neuroscience.2009.158(4):1469-1477.
[69] Kouranova, E.V., Strassle, B.W., Ring, R.H., et al. Hyperpolarization-activated cyclicnucleotide-gated channel mRNA and protein expression in large versus smalldiameter dorsal root ganglion neurons: correlation with hyperpolarization-activatedcurrent gating. Neuroscience.2008.153(4):1008-1019.
[70] Ludwig, A., Herrmann, S., Hoesl, E., et al. Mouse models for studying pacemakerchannel function and sinus node arrhythmia. Prog Biophys Mol Biol.2008.98(2-3):179-185.
[71] Stieber, J., Herrmann, S., Feil, S., et al. The hyperpolarization-activated channelHCN4is required for the generation of pacemaker action potentials in theembryonic heart. Proc Natl Acad Sci U S A.2003.100(25):15235-15240.
[72] Brown, H., Difrancesco, D., and Noble, S. Cardiac pacemaker oscillation and itsmodulation by autonomic transmitters. J Exp Biol.1979.81:175-204.
[73] Difrancesco, D. and Ferroni, A. Delayed activation of the cardiac pacemaker currentand its dependence on conditioning pre-hyperpolarizations. Pflugers Arch.1983.396(3):265-267.
[74] Difrancesco, D. Properties of the cardiac pacemaker (if) current. Boll Soc Ital BiolSper.1984.60Suppl4:29-33.
[75] Siu, C.W., Lieu, D.K., and Li, R.A. HCN-encoded pacemaker channels: fromphysiology and biophysics to bioengineering. J Membr Biol.2006.214(3):115-122.
[76] Choate, J.K., Nandhabalan, M., and Paterson, D.J. Raised extracellular potassiumattenuates the sympathetic modulation of sino-atrial node pacemaking in theisolated guinea-pig atria. Exp Physiol.2001.86(1):19-25.
[77] Michels, G., Er, F., Khan, I., et al. Single-channel properties support a potentialcontribution of hyperpolarization-activated cyclic nucleotide-gated channels and Ifto cardiac arrhythmias. Circulation.2005.111(4):399-404.
[78] Gasparini, S. and Difrancesco, D. Action of the hyperpolarization-activated current(Ih) blocker ZD7288in hippocampal CA1neurons. Pflugers Arch.1997.435(1):99-106.
[79] Shin, K.S., Rothberg, B.S., and Yellen, G. Blocker state dependence and trapping inhyperpolarization-activated cation channels: evidence for an intracellularactivation gate. J Gen Physiol.2001.117(2):91-101.
[80] Difrancesco, D. Some properties of the UL-FS49block of thehyperpolarization-activated current (i(f)) in sino-atrial node myocytes. PflugersArch.1994.427(1-2):64-70.
[81] Goethals, M., Raes, A., and Van Bogaert, P.P. Use-dependent block of the pacemakercurrent I(f) in rabbit sinoatrial node cells by zatebradine (UL-FS49). On the modeof action of sinus node inhibitors. Circulation.1993.88(5Pt1):2389-2401.
[82] Bois, P., Bescond, J., Renaudon, B., et al. Mode of action of bradycardic agent, S16257, on ionic currents of rabbit sinoatrial node cells. Br J Pharmacol.1996.118(4):1051-1057.
[83] Zagotta, W.N., Olivier, N.B., Black, K.D., et al. Structural basis for modulation andagonist specificity of HCN pacemaker channels. Nature.2003.425(6954):200-205.
[84] Pian, P., Bucchi, A., Decostanzo, A., et al. Modulation of cyclic nucleotide-regulatedHCN channels by PIP(2) and receptors coupled to phospholipase C. Pflugers Arch.2007.455(1):125-145.
[85] Huang, J., Huang, A., Zhang, Q., et al. Novel mechanism for suppression ofhyperpolarization-activated cyclic nucleotide-gated pacemaker channels byreceptor-like tyrosine phosphatase-alpha. J Biol Chem.2008.283(44):29912-29919.
[86] Gauss, R. and Seifert, R. Pacemaker oscillations in heart and brain: a key role forhyperpolarization-activated cation channels. Chronobiol Int.2000.17(4):453-469.
[87] Meuth, S.G., Kanyshkova, T., Meuth, P., et al. Membrane resting potential ofthalamocortical relay neurons is shaped by the interaction among TASK3andHCN2channels. J Neurophysiol.2006.96(3):1517-1529.
[88] Robinson, R.B. and Siegelbaum, S.A. Hyperpolarization-activated cation currents:from molecules to physiological function. Annu Rev Physiol.2003.65:453-480.
[89] Wahl-Schott, C. and Biel, M. HCN channels: structure, cellular regulation andphysiological function. Cell Mol Life Sci.2009.66(3):470-494.
[90] Papp, I., Szucs, P., Hollo, K., et al. Hyperpolarization-activated and cyclicnucleotide-gated cation channel subunit2ion channels modulate synaptictransmission from nociceptive primary afferents containing substance P tosecondary sensory neurons in laminae I-IIo of the rodent spinal dorsal horn. Eur JNeurosci.2006.24(5):1341-1352.
[91] Boyett, M.R., Honjo, H., and Kodama, I. The sinoatrial node, a heterogeneouspacemaker structure. Cardiovasc Res.2000.47(4):658-687.
[92] Raman, I.M. and Bean, B.P. Ionic currents underlying spontaneous action potentialsin isolated cerebellar Purkinje neurons. J Neurosci.1999.19(5):1663-1674.
[93] Thoby-Brisson, M., Telgkamp, P., and Ramirez, J.M. The role of thehyperpolarization-activated current in modulating rhythmic activity in the isolatedrespiratory network of mice. J Neurosci.2000.20(8):2994-3005.
[94] Chapman, C.A. and Lacaille, J.C. Intrinsic theta-frequency membrane potentialoscillations in hippocampal CA1interneurons of stratum lacunosum-moleculare. JNeurophysiol.1999.81(3):1296-1307.
[95] Williams, S.R., Christensen, S.R., Stuart, G.J., et al. Membrane potential bistability iscontrolled by the hyperpolarization-activated current I(H) in rat cerebellar Purkinjeneurons in vitro. J Physiol.2002.539(Pt2):469-483.
[96] Craven, K.B. and Zagotta, W.N. CNG and HCN channels: two peas, one pod. AnnuRev Physiol.2006.68:375-401.
[97] Vemana, S., Pandey, S., and Larsson, H.P. S4movement in a mammalian HCNchannel. J Gen Physiol.2004.123(1):21-32.
[98] Bell, D.C., Yao, H., Saenger, R.C., et al. Changes in local S4environment provide avoltage-sensing mechanism for mammalian hyperpolarization-activated HCNchannels. J Gen Physiol.2004.123(1):5-19.
[99] Moosmang, S., Stieber, J., Zong, X., et al. Cellular expression and functionalcharacterization of four hyperpolarization-activated pacemaker channels in cardiacand neuronal tissues. Eur J Biochem.2001.268(6):1646-1652.
[100] Shi, W., Wymore, R., Yu, H., et al. Distribution and prevalence ofhyperpolarization-activated cation channel (HCN) mRNA expression in cardiactissues. Circ Res.1999.85(1): e1-6.
[101] Robinson, R.B., Yu, H., Chang, F., et al. Developmental change in thevoltage-dependence of the pacemaker current, if, in rat ventricle cells. PflugersArch.1997.433(4):533-535.
[102] Biel, M., Schneider, A., and Wahl, C. Cardiac HCN channels: structure, function,and modulation. Trends Cardiovasc Med.2002.12(5):206-212.
[103] Ulens, C. and Tytgat, J. Functional heteromerization of HCN1and HCN2pacemaker channels. J Biol Chem.2001.276(9):6069-6072.
[104] Xue, T., Marban, E., and Li, R.A. Dominant-negative suppression of HCN1-andHCN2-encoded pacemaker currents by an engineered HCN1construct: insightsinto structure-function relationships and multimerization. Circ Res.2002.90(12):1267-1273.
[105] Yu, H., Wu, J., Potapova, I., et al. MinK-related peptide1: A beta subunit for theHCN ion channel subunit family enhances expression and speeds activation. CircRes.2001.88(12): E84-87.
[106] Bader, C.R., Macleish, P.R., and Schwartz, E.A. A voltage-clamp study of the lightresponse in solitary rods of the tiger salamander. J Physiol.1979.296:1-26.
[107] Viana, F., De La Pena, E., and Belmonte, C. Specificity of cold thermotransductionis determined by differential ionic channel expression. Nat Neurosci.2002.5(3):254-260.
[108] Stevens, D.R., Seifert, R., Bufe, B., et al. Hyperpolarization-activated channelsHCN1and HCN4mediate responses to sour stimuli. Nature.2001.413(6856):631-635.
[109] Santoro, B., Grant, S.G., Bartsch, D., et al. Interactive cloning with the SH3domainof N-src identifies a new brain specific ion channel protein, with homology to eagand cyclic nucleotide-gated channels. Proc Natl Acad Sci U S A.1997.94(26):14815-14820.
[110] Andrasfalvy, B.K. and Magee, J.C. Distance-dependent increase in AMPA receptornumber in the dendrites of adult hippocampal CA1pyramidal neurons. J Neurosci.2001.21(23):9151-9159.
[111] Poolos, N.P., Migliore, M., and Johnston, D. Pharmacological upregulation ofh-channels reduces the excitability of pyramidal neuron dendrites. Nat Neurosci.2002.5(8):767-774.
[112] Ulrich, D. Dendritic resonance in rat neocortical pyramidal cells. J Neurophysiol.2002.87(6):2753-2759.
[113] Brown, H. and Difrancesco, D. Voltage-clamp investigations of membrane currentsunderlying pace-maker activity in rabbit sino-atrial node. J Physiol.1980.308:331-351.
[114] Qu, J., Barbuti, A., Protas, L., et al. HCN2overexpression in newborn and adultventricular myocytes: distinct effects on gating and excitability. Circ Res.2001.89(1): E8-14.
[115] Difrancesco, D., Ducouret, P., and Robinson, R.B. Muscarinic modulation of cardiacrate at low acetylcholine concentrations. Science.1989.243(4891):669-671.
[116] Ranjan, R., Chiamvimonvat, N., Thakor, N.V., et al. Mechanism of anode breakstimulation in the heart. Biophys J.1998.74(4):1850-1863.
[117] Bal, T. and Mccormick, D.A. Synchronized oscillations in the inferior olive arecontrolled by the hyperpolarization-activated cation current I(h). J Neurophysiol.1997.77(6):3145-3156.
[118] Mccormick, D.A. and Bal, T. Sleep and arousal: thalamocortical mechanisms. AnnuRev Neurosci.1997.20:185-215.
[119] Luthi, A. and Mccormick, D.A. Modulation of a pacemaker current throughCa(2+)-induced stimulation of cAMP production. Nat Neurosci.1999.2(7):634-641.
[120] Dickson, C.T., Magistretti, J., Shalinsky, M.H., et al. Properties and role of I(h) inthe pacing of subthreshold oscillations in entorhinal cortex layer II neurons. JNeurophysiol.2000.83(5):2562-2579.
[121] Cuttle, M.F., Rusznak, Z., Wong, A.Y., et al. Modulation of a presynaptichyperpolarization-activated cationic current (I(h)) at an excitatory synapticterminal in the rat auditory brainstem. J Physiol.2001.534(Pt3):733-744.
[122] Chevaleyre, V. and Castillo, P.E. Assessing the role of Ih channels in synaptictransmission and mossy fiber LTP. Proc Natl Acad Sci U S A.2002.99(14):9538-9543.
[123] Demontis, G.C., Moroni, A., Gravante, B., et al. Functional characterisation andsubcellular localisation of HCN1channels in rabbit retinal rod photoreceptors. JPhysiol.2002.542(Pt1):89-97.
[124] Bender, R.A., Soleymani, S.V., Brewster, A.L., et al. Enhanced expression of aspecific hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN)in surviving dentate gyrus granule cells of human and experimental epileptichippocampus. J Neurosci.2003.23(17):6826-6836.
[125] Holderith, N.B., Shigemoto, R., and Nusser, Z. Cell type-dependent expression ofHCN1in the main olfactory bulb. Eur J Neurosci.2003.18(2):344-354.
[126] Santoro, B., Chen, S., Luthi, A., et al. Molecular and functional heterogeneity ofhyperpolarization-activated pacemaker channels in the mouse CNS. J Neurosci.2000.20(14):5264-5275.
[127] Moosmang, S., Biel, M., Hofmann, F., et al. Differential distribution of fourhyperpolarization-activated cation channels in mouse brain. Biol Chem.1999.380(7-8):975-980.
[128] Monteggia, L.M., Eisch, A.J., Tang, M.D., et al. Cloning and localization of thehyperpolarization-activated cyclic nucleotide-gated channel family in rat brain.Brain Res Mol Brain Res.2000.81(1-2):129-139.
[129] Lewis, A.S., Vaidya, S.P., Blaiss, C.A., et al. Deletion of thehyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunitTRIP8b impairs hippocampal Ih localization and function and promotesantidepressant behavior in mice. J Neurosci.2011.31(20):7424-7440.
[130] Atkinson, S.E. and Williams, S.R. Postnatal development of dendritic synapticintegration in rat neocortical pyramidal neurons. J Neurophysiol.2009.102(2):735-751.
[131] Battefeld, A., Rocha, N., Stadler, K., et al. Distinct perinatal features of thehyperpolarization-activated non-selective cation current Ih in the rat cortical plate.Neural Dev.2012.7(1):21.
[132] Hofmann, F., Fabritz, L., Stieber, J., et al. Ventricular HCN channels decrease therepolarization reserve in the hypertrophic heart. Cardiovasc Res.2012.95(3):317-326.
[133] Shah, M.M., Huang, Z., and Martinello, K. HCN and K(V)7(M-) channels astargets for epilepsy treatment. Neuropharmacology.2012.
[134] Emery, E.C., Young, G.T., Berrocoso, E.M., et al. HCN2ion channels play a centralrole in inflammatory and neuropathic pain. Science.2011.333(6048):1462-1466.
[135] Difrancesco, J.C., Barbuti, A., Milanesi, R., et al. Recessive loss-of-functionmutation in the pacemaker HCN2channel causing increased neuronal excitabilityin a patient with idiopathic generalized epilepsy. J Neurosci.2011.31(48):17327-17337.
[136] Almanza, A., Luis, E., Mercado, F., et al. Molecular identity, ontogeny, and cAMPmodulation of the hyperpolarization-activated current in vestibular ganglionneurons. J Neurophysiol.2012.108(8):2264-2275.
[137] Vandamme, J., Castermans, D., and Thevelein, J.M. Molecular mechanisms offeedback inhibition of protein kinase A on intracellular cAMP accumulation. CellSignal.2012.24(8):1610-1618.
[138] Simeone, T.A., Rho, J.M., and Baram, T.Z. Single channel properties ofhyperpolarization-activated cation currents in acutely dissociated rat hippocampalneurones. J Physiol.2005.568(Pt2):371-380.
[139] Hagiwara, N. and Irisawa, H. Modulation by intracellular Ca2+of thehyperpolarization-activated inward current in rabbit single sino-atrial node cells. JPhysiol.1989.409:121-141.
[140] Liao, Z., Lockhead, D., Larson, E.D., et al. Phosphorylation and modulation ofhyperpolarization-activated HCN4channels by protein kinase A in the mousesinoatrial node. J Gen Physiol.2010.136(3):247-258.
[141] Billington, C.K., Ojo, O.O., Penn, R.B., et al. cAMP regulation of airway smoothmuscle function. Pulm Pharmacol Ther.2013.26(1):112-120.
[142] Lania, A., Mantovani, G., and Spada, A. cAMP pathway and pituitary tumorigenesis.Ann Endocrinol (Paris).2012.73(2):73-75.
[143] Kronstad, J.W., Hu, G., and Choi, J. The cAMP/Protein Kinase A Pathway andVirulence in Cryptococcus neoformans. Mycobiology.2011.39(3):143-150.
[144] Zong, X., Krause, S., Chen, C.C., et al. Regulation of hyperpolarization-activatedcyclic nucleotide-gated (HCN) channel activity by cCMP. J Biol Chem.2012.287(32):26506-26512.
[145] Gao, L.L., Mcmullan, S., Djouhri, L., et al. Expression and properties ofhyperpolarization-activated current in rat dorsal root ganglion neurons with knownsensory function. J Physiol.2012.590(Pt19):4691-4705.
[146] Chen, X., Sirois, J.E., Lei, Q., et al. HCN subunit-specific and cAMP-modulatedeffects of anesthetics on neuronal pacemaker currents. J Neurosci.2005.25(24):5803-5814.
[147] Sung, T.S., Jeon, J.P., Kim, B.J., et al. Molecular determinants of PKA-dependentinhibition of TRPC5channel. Am J Physiol Cell Physiol.2011.301(4): C823-832.
[148] Wang, S., Xu, D.J., Cai, J.B., et al. Rapid component I(Kr) of cardiac delayedrectifier potassium currents in guinea-pig is inhibited by alpha(1)-adrenoreceptoractivation via protein kinase A and protein kinase C-dependent pathways. Eur JPharmacol.2009.608(1-3):1-6.
[149] Miller, R.J., Jung, H., Bhangoo, S.K., et al. Cytokine and chemokine regulation ofsensory neuron function. Handb Exp Pharmacol.2009(194):417-449.
[150] Dib-Hajj, S.D., Yang, Y., and Waxman, S.G. Genetics and molecularpathophysiology of Na(v)1.7-related pain syndromes. Adv Genet.2008.63:85-110.
[151] Xu, D., Wu, X., Grabauskas, G., et al. Butyrate-induced colonic hypersensitivity ismediated by mitogen-activated protein kinase activation in rat dorsal root ganglia.Gut.2012.
[152] Sun, B., Li, Q., Dong, L., et al. Ion channel and receptor mechanisms of bladderafferent nerve sensitivity. Auton Neurosci.2010.153(1-2):26-32.
[153] Han, C., Hoeijmakers, J.G., Ahn, H.S., et al. Nav1.7-related small fiber neuropathy:impaired slow-inactivation and DRG neuron hyperexcitability. Neurology.2012.78(21):1635-1643.
[154] Cao, X.H., Chen, S.R., Li, L., et al. Nerve injury increases brain-derivedneurotrophic factor levels to suppress BK channel activity in primary sensoryneurons. J Neurochem.2012.121(6):944-953.
[155] Lee, J., Kim, T., Hong, J., et al. Imiquimod enhances excitability of dorsal rootganglion neurons by inhibiting background (K(2P)) and voltage-gated (K(v)1.1and K(v)1.2) potassium channels. Mol Pain.2012.8:2.
[156] Wan, Y. Involvement of hyperpolarization-activated, cyclic nucleotide-gated cationchannels in dorsal root ganglion in neuropathic pain. Sheng Li Xue Bao.2008.60(5):579-580.
[157] Wang, Y.P., Sun, B.Y., Li, Q., et al. Hyperpolarization-activated cyclicnucleotide-gated cation channel subtypes differentially modulate the excitability ofmurine small intestinal afferents. World J Gastroenterol.2012.18(6):522-531.
[158] Weng, X., Smith, T., Sathish, J., et al. Chronic inflammatory pain is associated withincreased excitability and hyperpolarization-activated current (Ih) in C-but notAdelta-nociceptors. Pain.2012.153(4):900-914.
[159] Michels, G., Er, F., Khan, I.F., et al. K+channel regulator KCR1suppresses heartrhythm by modulating the pacemaker current If. PLoS One.2008.3(1): e1511.
[160] Leybaert, L. and Sanderson, M.J. Intercellular Ca(2+) waves: mechanisms andfunction. Physiol Rev.2012.92(3):1359-1392.
[161] Skupin, A. and Thurley, K. Calcium signaling: from single channels to pathways.Adv Exp Med Biol.2012.740:531-551.
[162] Wang, F., Zhang, Y., Jiang, X., et al. Neuromedin U inhibits T-type Ca2+channelcurrents and decreases membrane excitability in small dorsal root ganglia neuronsin mice. Cell Calcium.2011.49(1):12-22.
[163] Hou, L. and Wang, X. PKC and PKA, but not PKG mediate LPS-induced CGRPrelease and [Ca(2+)](i) elevation in DRG neurons of neonatal rats. J Neurosci Res.2001.66(4):592-600.
[164] Kryukova, Y.N., Protas, L., and Robinson, R.B. Ca2+-activated adenylyl cyclase1introduces Ca2+-dependence to beta-adrenergic stimulation of HCN2current. JMol Cell Cardiol.2012.52(6):1233-1239.
[165] Torrance, N., Smith, B.H., Bennett, M.I., et al. The epidemiology of chronic pain ofpredominantly neuropathic origin. Results from a general population survey. J Pain.2006.7(4):281-289.
[166] Bouhassira, D., Lanteri-Minet, M., Attal, N., et al. Prevalence of chronic pain withneuropathic characteristics in the general population. Pain.2008.136(3):380-387.
[167] Schmidt, R., Kleggetveit, I.P., Namer, B., et al. Double spikes to single electricalstimulation correlates to spontaneous activity of nociceptors in painful neuropathypatients. Pain.2012.153(2):391-398.
[168] Liu, M. and Wood, J.N. The roles of sodium channels in nociception: implicationsfor mechanisms of neuropathic pain. Pain Med.2011.12Suppl3: S93-99.
[169] Pexton, T., Moeller-Bertram, T., Schilling, J.M., et al. Targeting voltage-gatedcalcium channels for the treatment of neuropathic pain: a review of drugdevelopment. Expert Opin Investig Drugs.2011.20(9):1277-1284.
[170] Takeda, M., Tsuboi, Y., Kitagawa, J., et al. Potassium channels as a potentialtherapeutic target for trigeminal neuropathic and inflammatory pain. Mol Pain.2011.7:5.
[171] Nassar, M.A., Baker, M.D., Levato, A., et al. Nerve injury induces robust allodyniaand ectopic discharges in Nav1.3null mutant mice. Mol Pain.2006.2:33.
[172] Hains, B.C., Saab, C.Y., and Waxman, S.G. Changes in electrophysiologicalproperties and sodium channel Nav1.3expression in thalamic neurons after spinalcord injury. Brain.2005.128(Pt10):2359-2371.
[173] Diatchenko, L., Nackley, A.G., Tchivileva, I.E., et al. Genetic architecture of humanpain perception. Trends Genet.2007.23(12):605-613.
[174] Thakor, D.K., Lin, A., Matsuka, Y., et al. Increased peripheral nerve excitability andlocal NaV1.8mRNA up-regulation in painful neuropathy. Mol Pain.2009.5:14.
[175] Altier, C., Dale, C.S., Kisilevsky, A.E., et al. Differential role of N-type calciumchannel splice isoforms in pain. J Neurosci.2007.27(24):6363-6373.
[176] Dogrul, A., Yesilyurt, O., Isimer, A., et al. L-type and T-type calcium channelblockade potentiate the analgesic effects of morphine and selective mu opioidagonist, but not to selective delta and kappa agonist at the level of the spinal cordin mice. Pain.2001.93(1):61-68.
[177] Cheong, E., Lee, S., Choi, B.J., et al. Tuning thalamic firing modes via simultaneousmodulation of T-and L-type Ca2+channels controls pain sensory gating in thethalamus. J Neurosci.2008.28(49):13331-13340.
[178] Matsuyoshi, H., Masuda, N., Chancellor, M.B., et al. Expression ofhyperpolarization-activated cyclic nucleotide-gated cation channels in rat dorsalroot ganglion neurons innervating urinary bladder. Brain Res.2006.1119(1):115-123.
[179] Omana-Zapata, I. and Bley, K.R. A stable prostacyclin analog enhances ectopicactivity in rat sensory neurons following neuropathic injury. Brain Res.2001.904(1):85-92.
[180] Baruscotti, M. and Difrancesco, D. Pacemaker channels. Ann N Y Acad Sci.2004.1015:111-121.
[181] Biel, M., Wahl-Schott, C., Michalakis, S., et al. Hyperpolarization-activated cationchannels: from genes to function. Physiol Rev.2009.89(3):847-885.
[182] Takasu, K., Ono, H., and Tanabe, M. Spinal hyperpolarization-activated cyclicnucleotide-gated cation channels at primary afferent terminals contribute tochronic pain. Pain.2010.151(1):87-96.
[183] Koncz, I., Szel, T., Jaeger, K., et al. Selective pharmacological inhibition of thepacemaker channel isoforms (HCN1-4) as new possible therapeutical targets. CurrMed Chem.2011.18(24):3662-3674.
[184] Song, Y., Li, H.M., Xie, R.G., et al. Evoked bursting in injured Abeta dorsal rootganglion neurons: a mechanism underlying tactile allodynia. Pain.2012.153(3):657-665.
[185] Hatch, R.J., Jennings, E.A., and Ivanusic, J.J. Peripheral hyperpolarization-activatedcyclic nucleotide-gated channels contribute to inflammation-inducedhypersensitivity of the rat temporomandibular joint. Eur J Pain.2012.
[186] Emery, E.C., Young, G.T., and Mcnaughton, P.A. HCN2ion channels: an emergingrole as the pacemakers of pain. Trends Pharmacol Sci.2012.33(8):456-463.
[187] Decosterd, I. and Woolf, C.J. Spared nerve injury: an animal model of persistentperipheral neuropathic pain. Pain.2000.87(2):149-158.
[188] Vasilyev, D.V., Shan, Q., Lee, Y., et al. Direct inhibition of Ih by analgesicloperamide in rat DRG neurons. J Neurophysiol.2007.97(5):3713-3721.
[189] Djouhri, L., Fang, X., Koutsikou, S., et al. Partial nerve injury induceselectrophysiological changes in conducting (uninjured) nociceptive andnonnociceptive DRG neurons: Possible relationships to aspects of peripheralneuropathic pain and paresthesias. Pain.2012.153(9):1824-1836.
[190] Chaplan, S.R., Guo, H.Q., Lee, D.H., et al. Neuronal hyperpolarization-activatedpacemaker channels drive neuropathic pain. J Neurosci.2003.23(4):1169-1178.
[191] Yao, H., Donnelly, D.F., Ma, C., et al. Upregulation of thehyperpolarization-activated cation current after chronic compression of the dorsalroot ganglion. J Neurosci.2003.23(6):2069-2074.
[192] Kitagawa, J., Takeda, M., Suzuki, I., et al. Mechanisms involved in modulation oftrigeminal primary afferent activity in rats with peripheral mononeuropathy. Eur JNeurosci.2006.24(7):1976-1986.
[193] Jiang, Y.Q., Xing, G.G., Wang, S.L., et al. Axonal accumulation ofhyperpolarization-activated cyclic nucleotide-gated cation channels contributes tomechanical allodynia after peripheral nerve injury in rat. Pain.2008.137(3):495-506.
[194] Papp, I., Hollo, K., and Antal, M. Plasticity of hyperpolarization-activated andcyclic nucleotid-gated cation channel subunit2expression in the spinal dorsal hornin inflammatory pain. Eur J Neurosci.2010.32(7):1193-1201.
[195] Kajander, K.C. and Bennett, G.J. Onset of a painful peripheral neuropathy in rat: apartial and differential deafferentation and spontaneous discharge in A beta and Adelta primary afferent neurons. J Neurophysiol.1992.68(3):734-744.
[196] Liu, C.N., Wall, P.D., Ben-Dor, E., et al. Tactile allodynia in the absence of C-fiberactivation: altered firing properties of DRG neurons following spinal nerve injury.Pain.2000.85(3):503-521.
[197] Acosta, C., Mcmullan, S., Djouhri, L., et al. HCN1and HCN2in Rat DRG neurons:levels in nociceptors and non-nociceptors, NT3-dependence and influence ofCFA-induced skin inflammation on HCN2and NT3expression. PLoS One.2012.7(12): e50442.
[198] Jolly, M. Association of rheumatologic disease with preeclampsia. Obstet Gynecol.2004.104(5Pt1):1105-1106; author reply1106.
[199] Ma, C. and Lamotte, R.H. Multiple sites for generation of ectopic spontaneousactivity in neurons of the chronically compressed dorsal root ganglion. J Neurosci.2007.27(51):14059-14068.
[200] Devor, M. Ectopic discharge in Abeta afferents as a source of neuropathic pain. ExpBrain Res.2009.196(1):115-128.
[201] Tu, H., Deng, L., Sun, Q., et al. Hyperpolarization-activated, cyclic nucleotide-gatedcation channels: roles in the differential electrophysiological properties of ratprimary afferent neurons. J Neurosci Res.2004.76(5):713-722.
[202] Zhu, Y.F. and Henry, J.L. Excitability of Abeta sensory neurons is altered in ananimal model of peripheral neuropathy. BMC Neurosci.2012.13:15.
[203] Scheindlin, S. Ephedra: once a boon, now a bane. Mol Interv.2003.3(7):358-360.
[204] Charlton, S.T., Davis, S.S., and Illum, L. Evaluation of effect of ephedrine on thetransport of drugs from the nasal cavity to the systemic circulation and the centralnervous system. J Drug Target.2007.15(5):370-377.
[205] Langendijk, P.N. and Wilde, A.A.[Medication for ADHD and the risk ofcardiovascular mortality]. Ned Tijdschr Geneeskd.2006.150(31):1713-1714.
[206] Howden, R., Hanlon, P.R., Petranka, J.G., et al. Ephedrine plus caffeine causesage-dependent cardiovascular responses in Fischer344rats. Am J Physiol HeartCirc Physiol.2005.288(5): H2219-2224.
[207] Waluga, M., Janusz, M., Karpel, E., et al. Cardiovascular effects of ephedrine,caffeine and yohimbine measured by thoracic electrical bioimpedance in obesewomen. Clin Physiol.1998.18(1):69-76.
[208] Torpy, J.M., Lynm, C., and Glass, R.M. JAMA patient page. Ephedra and ephedrine.Jama.2003.289(12):1590.
[209] Adamson, P.B., Suarez, J., Ellis, E., et al. Ephedrine increases ventriculararrhythmias in conscious dogs after myocardial infarction. J Am Coll Cardiol.2004.44(8):1675-1678.
[210] Rosenbaum, T. and Gordon, S.E. Quickening the pace: looking into the heart ofHCN channels. Neuron.2004.42(2):193-196.
[211] Hung, Y.C., Kau, Y.C., Zizza, A.M., et al. Ephedrine blocks rat sciatic nerve in vivoand sodium channels in vitro. Anesthesiology.2005.103(6):1246-1252.
[212] Barbuti, A., Baruscotti, M., Altomare, C., et al. Action of internal pronase on thef-channel kinetics in the rabbit SA node. J Physiol.1999.520Pt3:737-744.
[213] Ishii, T.M., Takano, M., Xie, L.H., et al. Molecular characterization of thehyperpolarization-activated cation channel in rabbit heart sinoatrial node. J BiolChem.1999.274(18):12835-12839.
[214] Moroni, A., Barbuti, A., Altomare, C., et al. Kinetic and ionic properties of thehuman HCN2pacemaker channel. Pflugers Arch.2000.439(5):618-626.
[2] Valiyaveetil, F.I., Zhou, Y., and Mackinnon, R. Lipids in the structure, folding, andfunction of the KcsA K+channel. Biochemistry.2002.41(35):10771-10777.
[3] Long, S.B., Campbell, E.B., and Mackinnon, R. Crystal structure of a mammalianvoltage-dependent Shaker family K+channel. Science.2005.309(5736):897-903.
[4] Jiang, Y., Lee, A., Chen, J., et al. Crystal structure and mechanism of a calcium-gatedpotassium channel. Nature.2002.417(6888):515-522.
[5] Lee, S.Y., Lee, A., Chen, J., et al. Structure of the KvAP voltage-dependent K+channel and its dependence on the lipid membrane. Proc Natl Acad Sci U S A.2005.102(43):15441-15446.
[6] Nishida, M., Cadene, M., Chait, B.T., et al. Crystal structure of a Kir3.1-prokaryoticKir channel chimera. Embo J.2007.26(17):4005-4015.
[7] Jiang, Y., Lee, A., Chen, J., et al. X-ray structure of a voltage-dependent K+channel.Nature.2003.423(6935):33-41.
[8] Gulbis, J.M., Mann, S., and Mackinnon, R. Structure of a voltage-dependent K+channel beta subunit. Cell.1999.97(7):943-952.
[9] Gulbis, J.M., Zhou, M., Mann, S., et al. Structure of the cytoplasmic beta subunit-T1assembly of voltage-dependent K+channels. Science.2000.289(5476):123-127.
[10] Veizerova, L., Svetlik, J., and Kettmann, V. Voltage gated calcium channels: structure,characteristics and terminology. Ceska Slov Farm.2007.56(4):178-182.
[11] Bezanilla, F. The voltage-sensor structure in a voltage-gated channel. Trends BiochemSci.2005.30(4):166-168.
[12] Giorgi, C., Romagnoli, A., Pinton, P., et al. Ca2+signaling, mitochondria and celldeath. Curr Mol Med.2008.8(2):119-130.
[13] Belkacemi, L., Bedard, I., Simoneau, L., et al. Calcium channels, transporters andexchangers in placenta: a review. Cell Calcium.2005.37(1):1-8.
[14] Huc, S., Monteil, A., Bidaud, I., et al. Regulation of T-type calcium channels:Signalling pathways and functional implications. Biochim Biophys Acta.2008.
[15] Khosravani, H. and Zamponi, G.W. Voltage-gated calcium channels and idiopathicgeneralized epilepsies. Physiol Rev.2006.86(3):941-966.
[16] Treinys, R. and Jurevicius, J. L-type Ca2+channels in the heart: structure andregulation. Medicina (Kaunas).2008.44(7):491-499.
[17] Hofmann, F., Lacinova, L., and Klugbauer, N. Voltage-dependent calcium channels:from structure to function. Rev Physiol Biochem Pharmacol.1999.139:33-87.
[18] Haase, H., Pfitzmaier, B., Mcenery, M.W., et al. Expression of Ca(2+) channelsubunits during cardiac ontogeny in mice and rats: identification of fetal alpha(1C)and beta subunit isoforms. J Cell Biochem.2000.76(4):695-703.
[19] Hell, J.W., Westenbroek, R.E., Warner, C., et al. Identification and differentialsubcellular localization of the neuronal class C and class D L-type calcium channelalpha1subunits. J Cell Biol.1993.123(4):949-962.
[20] Baumann, L., Gerstner, A., Zong, X., et al. Functional characterization of the L-typeCa2+channel Cav1.4alpha1from mouse retina. Invest Ophthalmol Vis Sci.2004.45(2):708-713.
[21] Davis, M.J. and Hill, M.A. Signaling mechanisms underlying the vascular myogenicresponse. Physiol Rev.1999.79(2):387-423.
[22] Henquin, J.C. and Meissner, H.P. Significance of ionic fluxes and changes inmembrane potential for stimulus-secretion coupling in pancreatic B-cells.Experientia.1984.40(10):1043-1052.
[23] Frey, N., Mckinsey, T.A., and Olson, E.N. Decoding calcium signals involved incardiac growth and function. Nat Med.2000.6(11):1221-1227.
[24] Quartermain, D. Chronic administration of the Ca(2+) channel blocker amlodipinefacilitates learning and memory in mice. Eur J Pharmacol.2000.399(1):57-63.
[25] Woodside, B.L., Borroni, A.M., Hammonds, M.D., et al. NMDA receptors andvoltage-dependent calcium channels mediate different aspects of acquisition andretention of a spatial memory task. Neurobiol Learn Mem.2004.81(2):105-114.
[26] Bauer, E.P., Schafe, G.E., and Ledoux, J.E. NMDA receptors and L-typevoltage-gated calcium channels contribute to long-term potentiation and differentcomponents of fear memory formation in the lateral amygdala. J Neurosci.2002.22(12):5239-5249.
[27] Fox, A.P., Cahill, A.L., Currie, K.P., et al. N-and P/Q-type Ca2+channels in adrenalchromaffin cells. Acta Physiol (Oxf).2008.192(2):247-261.
[28] Gazulla, J. and Tintore, M.[P/Q-type voltage-dependent calcium channels inneurological disease]. Neurologia.2007.22(8):511-516.
[29] Gazulla, J. and Tintore, M. The P/Q-type voltage-dependent calcium channel: atherapeutic target in spinocerebellar ataxia type6. Acta Neurol Scand.2007.115(5):356-363.
[30] Janssen, L.J. and Kwan, C.Y. ROCs and SOCs: what's in a name? Cell Calcium.2007.41(3):245-247.
[31] Baranauskas, G. Ionic channel function in action potential generation: currentperspective. Mol Neurobiol.2007.35(2):129-150.
[32] Christe, G., Chahine, M., Chevalier, P., et al. Changes in action potentials andintracellular ionic homeostasis in a ventricular cell model related to a persistentsodium current in SCN5A mutations underlying LQT3. Prog Biophys Mol Biol.2008.96(1-3):281-293.
[33] Yamaoka, K., Vogel, S.M., and Seyama, I. Na+channel pharmacology and molecularmechanisms of gating. Curr Pharm Des.2006.12(4):429-442.
[34] Isom, L.L. Sodium channel beta subunits: anything but auxiliary. Neuroscientist.2001.7(1):42-54.
[35] Hanlon, M.R. and Wallace, B.A. Structure and function of voltage-dependent ionchannel regulatory beta subunits. Biochemistry.2002.41(9):2886-2894.
[36] Pfahnl, A.E., Viswanathan, P.C., Weiss, R., et al. A sodium channel pore mutationcausing Brugada syndrome. Heart Rhythm.2007.4(1):46-53.
[37] Goldin, A.L. Mechanisms of sodium channel inactivation. Curr Opin Neurobiol.2003.13(3):284-290.
[38] Blumenthal, K.M. and Seibert, A.L. Voltage-gated sodium channel toxins: poisons,probes, and future promise. Cell Biochem Biophys.2003.38(2):215-238.
[39] Cestele, S. and Catterall, W.A. Molecular mechanisms of neurotoxin action onvoltage-gated sodium channels. Biochimie.2000.82(9-10):883-892.
[40] Endoh, M. A Na+channel agonist: a potential cardiotonic agent with a novelmechanism? Br J Pharmacol.2004.143(6):663-665.
[41] Gonoi, T., Ohizumi, Y., Kobayashi, J., et al. Actions of a polypeptide toxin from themarine snail Conus striatus on voltage-sensitive sodium channels. Mol Pharmacol.1987.32(5):691-698.
[42] Noskov, S.Y. and Roux, B. Ion selectivity in potassium channels. Biophys Chem.2006.124(3):279-291.
[43] Mannhold, R. Structure-activity relationships of K(ATP) channel openers. Curr TopMed Chem.2006.6(10):1031-1047.
[44] Wang, Y., Cheng, J., Tandan, S., et al. Transient-outward K+channel inhibitionfacilitates L-type Ca2+current in heart. J Cardiovasc Electrophysiol.2006.17(3):298-304.
[45] Salkoff, L., Wei, A.D., Baban, B., et al. Potassium channels in C. elegans. WormBook.2005:1-15.
[46] Calloe, K., Cordeiro, J.M., Di Diego, J.M., et al. A transient outward potassiumcurrent activator recapitulates the electrocardiographic manifestations of Brugadasyndrome. Cardiovasc Res.2009.81(4):686-694.
[47] Bai, J., Ren, C., Hao, W., et al. Chemical sympathetic denervation, suppression ofmyocardial transient outward potassium current, and ventricular fibrillation in therat. Can J Physiol Pharmacol.2008.86(10):700-709.
[48] Wagner, M., Goltz, D., Stucke, C., et al. Modulation of the transient outward K+current by inhibition of endothelin-A receptors in normal and hypertrophied rathearts. Pflugers Arch.2007.454(4):595-604.
[49] Belugin, S. and Mifflin, S. Transient voltage-dependent potassium currents arereduced in NTS neurons isolated from renal wrap hypertensive rats. JNeurophysiol.2005.94(6):3849-3859.
[50] Fedida, D. and Hesketh, J.C. Gating of voltage-dependent potassium channels. ProgBiophys Mol Biol.2001.75(3):165-199.
[51] Gardiwal, A., Klein, G., Kraemer, K., et al. Reduced delayed rectifier K+current,altered electrophysiology, and increased ventricular vulnerability in MLP-deficientmice. J Card Fail.2007.13(8):687-693.
[52] Kofuji, P. and Newman, E.A. Potassium buffering in the central nervous system.Neuroscience.2004.129(4):1045-1056.
[53] Tada, Y., Horio, Y., and Kurachi, Y. Inwardly rectifying K+channel in retinal Mullercells: comparison with the KAB-2/Kir4.1channel expressed in HEK293T cells.Jpn J Physiol.1998.48(1):71-80.
[54] Benhassine, N. and Berger, T. Homogeneous distribution of large-conductancecalcium-dependent potassium channels on soma and apical dendrite of ratneocortical layer5pyramidal neurons. Eur J Neurosci.2005.21(4):914-926.
[55] Ghisdal, P. and Morel, N. Cellular target of voltage and calcium-dependent K(+)channel blockers involved in EDHF-mediated responses in rat superior mesentericartery. Br J Pharmacol.2001.134(5):1021-1028.
[56] Cornfield, D.N., Reeve, H.L., Tolarova, S., et al. Oxygen causes fetal pulmonaryvasodilation through activation of a calcium-dependent potassium channel. ProcNatl Acad Sci U S A.1996.93(15):8089-8094.
[57] Mital, S. and Konduri, G.G. Vascular potassium channels mediate oxygen-inducedpulmonary vasodilation in fetal lambs. Biol Neonate.2000.77(1):58-68.
[58] Jentsch, T.J. CLC chloride channels and transporters: from genes to protein structure,pathology and physiology. Crit Rev Biochem Mol Biol.2008.43(1):3-36.
[59] Vandewalle, A. Expression and function of CLC and cystic fibrosis transmembraneconductance regulator chloride channels in renal epithelial tubule cells:pathophysiological implications. Chang Gung Med J.2007.30(1):17-25.
[60] Lotshaw, D.P., Levitan, E.S., and Levitan, I.B. Fine tuning of neuronal electricalactivity: modulation of several ion channels by intracellular messengers in a singleidentified nerve cell. J Exp Biol.1986.124:307-322.
[61] Knauf, P.A. and Mann, N.A. Location of the chloride self-inhibitory site of the humanerythrocyte anion exchange system. Am J Physiol.1986.251(1Pt1): C1-9.
[62] Powell, K.L., Cain, S.M., Ng, C., et al. A Cav3.2T-type calcium channel pointmutation has splice-variant-specific effects on function and segregates with seizureexpression in a polygenic rat model of absence epilepsy. J Neurosci.2009.29(2):371-380.
[63] Saito, Y.A., Strege, P.R., Tester, D.J., et al. Sodium channel mutation in irritablebowel syndrome: evidence for an ion channelopathy. Am J Physiol GastrointestLiver Physiol.2009.296(2): G211-218.
[64] Teng, G.Q., Zhao, X., Lees-Miller, J.P., et al. Homozygous missense N629D hERG(KCNH2) potassium channel mutation causes developmental defects in the rightventricle and its outflow tract and embryonic lethality. Circ Res.2008.103(12):1483-1491.
[65] Noma, A. and Irisawa, H. Membrane currents in the rabbit sinoatrial node cell asstudied by the double microelectrode method. Pflugers Arch.1976.364(1):45-52.
[66] Brown, H.F., Difrancesco, D., and Noble, S.J. How does adrenaline accelerate theheart? Nature.1979.280(5719):235-236.
[67] Halliwell, J.V. and Adams, P.R. Voltage-clamp analysis of muscarinic excitation inhippocampal neurons. Brain Res.1982.250(1):71-92.
[68] Bakondi, G., Por, A., Kovacs, I., et al. Hyperpolarization-activated, cyclicnucleotide-gated, cation non-selective channel subunit expression pattern ofguinea-pig spiral ganglion cells. Neuroscience.2009.158(4):1469-1477.
[69] Kouranova, E.V., Strassle, B.W., Ring, R.H., et al. Hyperpolarization-activated cyclicnucleotide-gated channel mRNA and protein expression in large versus smalldiameter dorsal root ganglion neurons: correlation with hyperpolarization-activatedcurrent gating. Neuroscience.2008.153(4):1008-1019.
[70] Ludwig, A., Herrmann, S., Hoesl, E., et al. Mouse models for studying pacemakerchannel function and sinus node arrhythmia. Prog Biophys Mol Biol.2008.98(2-3):179-185.
[71] Stieber, J., Herrmann, S., Feil, S., et al. The hyperpolarization-activated channelHCN4is required for the generation of pacemaker action potentials in theembryonic heart. Proc Natl Acad Sci U S A.2003.100(25):15235-15240.
[72] Brown, H., Difrancesco, D., and Noble, S. Cardiac pacemaker oscillation and itsmodulation by autonomic transmitters. J Exp Biol.1979.81:175-204.
[73] Difrancesco, D. and Ferroni, A. Delayed activation of the cardiac pacemaker currentand its dependence on conditioning pre-hyperpolarizations. Pflugers Arch.1983.396(3):265-267.
[74] Difrancesco, D. Properties of the cardiac pacemaker (if) current. Boll Soc Ital BiolSper.1984.60Suppl4:29-33.
[75] Siu, C.W., Lieu, D.K., and Li, R.A. HCN-encoded pacemaker channels: fromphysiology and biophysics to bioengineering. J Membr Biol.2006.214(3):115-122.
[76] Choate, J.K., Nandhabalan, M., and Paterson, D.J. Raised extracellular potassiumattenuates the sympathetic modulation of sino-atrial node pacemaking in theisolated guinea-pig atria. Exp Physiol.2001.86(1):19-25.
[77] Michels, G., Er, F., Khan, I., et al. Single-channel properties support a potentialcontribution of hyperpolarization-activated cyclic nucleotide-gated channels and Ifto cardiac arrhythmias. Circulation.2005.111(4):399-404.
[78] Gasparini, S. and Difrancesco, D. Action of the hyperpolarization-activated current(Ih) blocker ZD7288in hippocampal CA1neurons. Pflugers Arch.1997.435(1):99-106.
[79] Shin, K.S., Rothberg, B.S., and Yellen, G. Blocker state dependence and trapping inhyperpolarization-activated cation channels: evidence for an intracellularactivation gate. J Gen Physiol.2001.117(2):91-101.
[80] Difrancesco, D. Some properties of the UL-FS49block of thehyperpolarization-activated current (i(f)) in sino-atrial node myocytes. PflugersArch.1994.427(1-2):64-70.
[81] Goethals, M., Raes, A., and Van Bogaert, P.P. Use-dependent block of the pacemakercurrent I(f) in rabbit sinoatrial node cells by zatebradine (UL-FS49). On the modeof action of sinus node inhibitors. Circulation.1993.88(5Pt1):2389-2401.
[82] Bois, P., Bescond, J., Renaudon, B., et al. Mode of action of bradycardic agent, S16257, on ionic currents of rabbit sinoatrial node cells. Br J Pharmacol.1996.118(4):1051-1057.
[83] Zagotta, W.N., Olivier, N.B., Black, K.D., et al. Structural basis for modulation andagonist specificity of HCN pacemaker channels. Nature.2003.425(6954):200-205.
[84] Pian, P., Bucchi, A., Decostanzo, A., et al. Modulation of cyclic nucleotide-regulatedHCN channels by PIP(2) and receptors coupled to phospholipase C. Pflugers Arch.2007.455(1):125-145.
[85] Huang, J., Huang, A., Zhang, Q., et al. Novel mechanism for suppression ofhyperpolarization-activated cyclic nucleotide-gated pacemaker channels byreceptor-like tyrosine phosphatase-alpha. J Biol Chem.2008.283(44):29912-29919.
[86] Gauss, R. and Seifert, R. Pacemaker oscillations in heart and brain: a key role forhyperpolarization-activated cation channels. Chronobiol Int.2000.17(4):453-469.
[87] Meuth, S.G., Kanyshkova, T., Meuth, P., et al. Membrane resting potential ofthalamocortical relay neurons is shaped by the interaction among TASK3andHCN2channels. J Neurophysiol.2006.96(3):1517-1529.
[88] Robinson, R.B. and Siegelbaum, S.A. Hyperpolarization-activated cation currents:from molecules to physiological function. Annu Rev Physiol.2003.65:453-480.
[89] Wahl-Schott, C. and Biel, M. HCN channels: structure, cellular regulation andphysiological function. Cell Mol Life Sci.2009.66(3):470-494.
[90] Papp, I., Szucs, P., Hollo, K., et al. Hyperpolarization-activated and cyclicnucleotide-gated cation channel subunit2ion channels modulate synaptictransmission from nociceptive primary afferents containing substance P tosecondary sensory neurons in laminae I-IIo of the rodent spinal dorsal horn. Eur JNeurosci.2006.24(5):1341-1352.
[91] Boyett, M.R., Honjo, H., and Kodama, I. The sinoatrial node, a heterogeneouspacemaker structure. Cardiovasc Res.2000.47(4):658-687.
[92] Raman, I.M. and Bean, B.P. Ionic currents underlying spontaneous action potentialsin isolated cerebellar Purkinje neurons. J Neurosci.1999.19(5):1663-1674.
[93] Thoby-Brisson, M., Telgkamp, P., and Ramirez, J.M. The role of thehyperpolarization-activated current in modulating rhythmic activity in the isolatedrespiratory network of mice. J Neurosci.2000.20(8):2994-3005.
[94] Chapman, C.A. and Lacaille, J.C. Intrinsic theta-frequency membrane potentialoscillations in hippocampal CA1interneurons of stratum lacunosum-moleculare. JNeurophysiol.1999.81(3):1296-1307.
[95] Williams, S.R., Christensen, S.R., Stuart, G.J., et al. Membrane potential bistability iscontrolled by the hyperpolarization-activated current I(H) in rat cerebellar Purkinjeneurons in vitro. J Physiol.2002.539(Pt2):469-483.
[96] Craven, K.B. and Zagotta, W.N. CNG and HCN channels: two peas, one pod. AnnuRev Physiol.2006.68:375-401.
[97] Vemana, S., Pandey, S., and Larsson, H.P. S4movement in a mammalian HCNchannel. J Gen Physiol.2004.123(1):21-32.
[98] Bell, D.C., Yao, H., Saenger, R.C., et al. Changes in local S4environment provide avoltage-sensing mechanism for mammalian hyperpolarization-activated HCNchannels. J Gen Physiol.2004.123(1):5-19.
[99] Moosmang, S., Stieber, J., Zong, X., et al. Cellular expression and functionalcharacterization of four hyperpolarization-activated pacemaker channels in cardiacand neuronal tissues. Eur J Biochem.2001.268(6):1646-1652.
[100] Shi, W., Wymore, R., Yu, H., et al. Distribution and prevalence ofhyperpolarization-activated cation channel (HCN) mRNA expression in cardiactissues. Circ Res.1999.85(1): e1-6.
[101] Robinson, R.B., Yu, H., Chang, F., et al. Developmental change in thevoltage-dependence of the pacemaker current, if, in rat ventricle cells. PflugersArch.1997.433(4):533-535.
[102] Biel, M., Schneider, A., and Wahl, C. Cardiac HCN channels: structure, function,and modulation. Trends Cardiovasc Med.2002.12(5):206-212.
[103] Ulens, C. and Tytgat, J. Functional heteromerization of HCN1and HCN2pacemaker channels. J Biol Chem.2001.276(9):6069-6072.
[104] Xue, T., Marban, E., and Li, R.A. Dominant-negative suppression of HCN1-andHCN2-encoded pacemaker currents by an engineered HCN1construct: insightsinto structure-function relationships and multimerization. Circ Res.2002.90(12):1267-1273.
[105] Yu, H., Wu, J., Potapova, I., et al. MinK-related peptide1: A beta subunit for theHCN ion channel subunit family enhances expression and speeds activation. CircRes.2001.88(12): E84-87.
[106] Bader, C.R., Macleish, P.R., and Schwartz, E.A. A voltage-clamp study of the lightresponse in solitary rods of the tiger salamander. J Physiol.1979.296:1-26.
[107] Viana, F., De La Pena, E., and Belmonte, C. Specificity of cold thermotransductionis determined by differential ionic channel expression. Nat Neurosci.2002.5(3):254-260.
[108] Stevens, D.R., Seifert, R., Bufe, B., et al. Hyperpolarization-activated channelsHCN1and HCN4mediate responses to sour stimuli. Nature.2001.413(6856):631-635.
[109] Santoro, B., Grant, S.G., Bartsch, D., et al. Interactive cloning with the SH3domainof N-src identifies a new brain specific ion channel protein, with homology to eagand cyclic nucleotide-gated channels. Proc Natl Acad Sci U S A.1997.94(26):14815-14820.
[110] Andrasfalvy, B.K. and Magee, J.C. Distance-dependent increase in AMPA receptornumber in the dendrites of adult hippocampal CA1pyramidal neurons. J Neurosci.2001.21(23):9151-9159.
[111] Poolos, N.P., Migliore, M., and Johnston, D. Pharmacological upregulation ofh-channels reduces the excitability of pyramidal neuron dendrites. Nat Neurosci.2002.5(8):767-774.
[112] Ulrich, D. Dendritic resonance in rat neocortical pyramidal cells. J Neurophysiol.2002.87(6):2753-2759.
[113] Brown, H. and Difrancesco, D. Voltage-clamp investigations of membrane currentsunderlying pace-maker activity in rabbit sino-atrial node. J Physiol.1980.308:331-351.
[114] Qu, J., Barbuti, A., Protas, L., et al. HCN2overexpression in newborn and adultventricular myocytes: distinct effects on gating and excitability. Circ Res.2001.89(1): E8-14.
[115] Difrancesco, D., Ducouret, P., and Robinson, R.B. Muscarinic modulation of cardiacrate at low acetylcholine concentrations. Science.1989.243(4891):669-671.
[116] Ranjan, R., Chiamvimonvat, N., Thakor, N.V., et al. Mechanism of anode breakstimulation in the heart. Biophys J.1998.74(4):1850-1863.
[117] Bal, T. and Mccormick, D.A. Synchronized oscillations in the inferior olive arecontrolled by the hyperpolarization-activated cation current I(h). J Neurophysiol.1997.77(6):3145-3156.
[118] Mccormick, D.A. and Bal, T. Sleep and arousal: thalamocortical mechanisms. AnnuRev Neurosci.1997.20:185-215.
[119] Luthi, A. and Mccormick, D.A. Modulation of a pacemaker current throughCa(2+)-induced stimulation of cAMP production. Nat Neurosci.1999.2(7):634-641.
[120] Dickson, C.T., Magistretti, J., Shalinsky, M.H., et al. Properties and role of I(h) inthe pacing of subthreshold oscillations in entorhinal cortex layer II neurons. JNeurophysiol.2000.83(5):2562-2579.
[121] Cuttle, M.F., Rusznak, Z., Wong, A.Y., et al. Modulation of a presynaptichyperpolarization-activated cationic current (I(h)) at an excitatory synapticterminal in the rat auditory brainstem. J Physiol.2001.534(Pt3):733-744.
[122] Chevaleyre, V. and Castillo, P.E. Assessing the role of Ih channels in synaptictransmission and mossy fiber LTP. Proc Natl Acad Sci U S A.2002.99(14):9538-9543.
[123] Demontis, G.C., Moroni, A., Gravante, B., et al. Functional characterisation andsubcellular localisation of HCN1channels in rabbit retinal rod photoreceptors. JPhysiol.2002.542(Pt1):89-97.
[124] Bender, R.A., Soleymani, S.V., Brewster, A.L., et al. Enhanced expression of aspecific hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN)in surviving dentate gyrus granule cells of human and experimental epileptichippocampus. J Neurosci.2003.23(17):6826-6836.
[125] Holderith, N.B., Shigemoto, R., and Nusser, Z. Cell type-dependent expression ofHCN1in the main olfactory bulb. Eur J Neurosci.2003.18(2):344-354.
[126] Santoro, B., Chen, S., Luthi, A., et al. Molecular and functional heterogeneity ofhyperpolarization-activated pacemaker channels in the mouse CNS. J Neurosci.2000.20(14):5264-5275.
[127] Moosmang, S., Biel, M., Hofmann, F., et al. Differential distribution of fourhyperpolarization-activated cation channels in mouse brain. Biol Chem.1999.380(7-8):975-980.
[128] Monteggia, L.M., Eisch, A.J., Tang, M.D., et al. Cloning and localization of thehyperpolarization-activated cyclic nucleotide-gated channel family in rat brain.Brain Res Mol Brain Res.2000.81(1-2):129-139.
[129] Lewis, A.S., Vaidya, S.P., Blaiss, C.A., et al. Deletion of thehyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunitTRIP8b impairs hippocampal Ih localization and function and promotesantidepressant behavior in mice. J Neurosci.2011.31(20):7424-7440.
[130] Atkinson, S.E. and Williams, S.R. Postnatal development of dendritic synapticintegration in rat neocortical pyramidal neurons. J Neurophysiol.2009.102(2):735-751.
[131] Battefeld, A., Rocha, N., Stadler, K., et al. Distinct perinatal features of thehyperpolarization-activated non-selective cation current Ih in the rat cortical plate.Neural Dev.2012.7(1):21.
[132] Hofmann, F., Fabritz, L., Stieber, J., et al. Ventricular HCN channels decrease therepolarization reserve in the hypertrophic heart. Cardiovasc Res.2012.95(3):317-326.
[133] Shah, M.M., Huang, Z., and Martinello, K. HCN and K(V)7(M-) channels astargets for epilepsy treatment. Neuropharmacology.2012.
[134] Emery, E.C., Young, G.T., Berrocoso, E.M., et al. HCN2ion channels play a centralrole in inflammatory and neuropathic pain. Science.2011.333(6048):1462-1466.
[135] Difrancesco, J.C., Barbuti, A., Milanesi, R., et al. Recessive loss-of-functionmutation in the pacemaker HCN2channel causing increased neuronal excitabilityin a patient with idiopathic generalized epilepsy. J Neurosci.2011.31(48):17327-17337.
[136] Almanza, A., Luis, E., Mercado, F., et al. Molecular identity, ontogeny, and cAMPmodulation of the hyperpolarization-activated current in vestibular ganglionneurons. J Neurophysiol.2012.108(8):2264-2275.
[137] Vandamme, J., Castermans, D., and Thevelein, J.M. Molecular mechanisms offeedback inhibition of protein kinase A on intracellular cAMP accumulation. CellSignal.2012.24(8):1610-1618.
[138] Simeone, T.A., Rho, J.M., and Baram, T.Z. Single channel properties ofhyperpolarization-activated cation currents in acutely dissociated rat hippocampalneurones. J Physiol.2005.568(Pt2):371-380.
[139] Hagiwara, N. and Irisawa, H. Modulation by intracellular Ca2+of thehyperpolarization-activated inward current in rabbit single sino-atrial node cells. JPhysiol.1989.409:121-141.
[140] Liao, Z., Lockhead, D., Larson, E.D., et al. Phosphorylation and modulation ofhyperpolarization-activated HCN4channels by protein kinase A in the mousesinoatrial node. J Gen Physiol.2010.136(3):247-258.
[141] Billington, C.K., Ojo, O.O., Penn, R.B., et al. cAMP regulation of airway smoothmuscle function. Pulm Pharmacol Ther.2013.26(1):112-120.
[142] Lania, A., Mantovani, G., and Spada, A. cAMP pathway and pituitary tumorigenesis.Ann Endocrinol (Paris).2012.73(2):73-75.
[143] Kronstad, J.W., Hu, G., and Choi, J. The cAMP/Protein Kinase A Pathway andVirulence in Cryptococcus neoformans. Mycobiology.2011.39(3):143-150.
[144] Zong, X., Krause, S., Chen, C.C., et al. Regulation of hyperpolarization-activatedcyclic nucleotide-gated (HCN) channel activity by cCMP. J Biol Chem.2012.287(32):26506-26512.
[145] Gao, L.L., Mcmullan, S., Djouhri, L., et al. Expression and properties ofhyperpolarization-activated current in rat dorsal root ganglion neurons with knownsensory function. J Physiol.2012.590(Pt19):4691-4705.
[146] Chen, X., Sirois, J.E., Lei, Q., et al. HCN subunit-specific and cAMP-modulatedeffects of anesthetics on neuronal pacemaker currents. J Neurosci.2005.25(24):5803-5814.
[147] Sung, T.S., Jeon, J.P., Kim, B.J., et al. Molecular determinants of PKA-dependentinhibition of TRPC5channel. Am J Physiol Cell Physiol.2011.301(4): C823-832.
[148] Wang, S., Xu, D.J., Cai, J.B., et al. Rapid component I(Kr) of cardiac delayedrectifier potassium currents in guinea-pig is inhibited by alpha(1)-adrenoreceptoractivation via protein kinase A and protein kinase C-dependent pathways. Eur JPharmacol.2009.608(1-3):1-6.
[149] Miller, R.J., Jung, H., Bhangoo, S.K., et al. Cytokine and chemokine regulation ofsensory neuron function. Handb Exp Pharmacol.2009(194):417-449.
[150] Dib-Hajj, S.D., Yang, Y., and Waxman, S.G. Genetics and molecularpathophysiology of Na(v)1.7-related pain syndromes. Adv Genet.2008.63:85-110.
[151] Xu, D., Wu, X., Grabauskas, G., et al. Butyrate-induced colonic hypersensitivity ismediated by mitogen-activated protein kinase activation in rat dorsal root ganglia.Gut.2012.
[152] Sun, B., Li, Q., Dong, L., et al. Ion channel and receptor mechanisms of bladderafferent nerve sensitivity. Auton Neurosci.2010.153(1-2):26-32.
[153] Han, C., Hoeijmakers, J.G., Ahn, H.S., et al. Nav1.7-related small fiber neuropathy:impaired slow-inactivation and DRG neuron hyperexcitability. Neurology.2012.78(21):1635-1643.
[154] Cao, X.H., Chen, S.R., Li, L., et al. Nerve injury increases brain-derivedneurotrophic factor levels to suppress BK channel activity in primary sensoryneurons. J Neurochem.2012.121(6):944-953.
[155] Lee, J., Kim, T., Hong, J., et al. Imiquimod enhances excitability of dorsal rootganglion neurons by inhibiting background (K(2P)) and voltage-gated (K(v)1.1and K(v)1.2) potassium channels. Mol Pain.2012.8:2.
[156] Wan, Y. Involvement of hyperpolarization-activated, cyclic nucleotide-gated cationchannels in dorsal root ganglion in neuropathic pain. Sheng Li Xue Bao.2008.60(5):579-580.
[157] Wang, Y.P., Sun, B.Y., Li, Q., et al. Hyperpolarization-activated cyclicnucleotide-gated cation channel subtypes differentially modulate the excitability ofmurine small intestinal afferents. World J Gastroenterol.2012.18(6):522-531.
[158] Weng, X., Smith, T., Sathish, J., et al. Chronic inflammatory pain is associated withincreased excitability and hyperpolarization-activated current (Ih) in C-but notAdelta-nociceptors. Pain.2012.153(4):900-914.
[159] Michels, G., Er, F., Khan, I.F., et al. K+channel regulator KCR1suppresses heartrhythm by modulating the pacemaker current If. PLoS One.2008.3(1): e1511.
[160] Leybaert, L. and Sanderson, M.J. Intercellular Ca(2+) waves: mechanisms andfunction. Physiol Rev.2012.92(3):1359-1392.
[161] Skupin, A. and Thurley, K. Calcium signaling: from single channels to pathways.Adv Exp Med Biol.2012.740:531-551.
[162] Wang, F., Zhang, Y., Jiang, X., et al. Neuromedin U inhibits T-type Ca2+channelcurrents and decreases membrane excitability in small dorsal root ganglia neuronsin mice. Cell Calcium.2011.49(1):12-22.
[163] Hou, L. and Wang, X. PKC and PKA, but not PKG mediate LPS-induced CGRPrelease and [Ca(2+)](i) elevation in DRG neurons of neonatal rats. J Neurosci Res.2001.66(4):592-600.
[164] Kryukova, Y.N., Protas, L., and Robinson, R.B. Ca2+-activated adenylyl cyclase1introduces Ca2+-dependence to beta-adrenergic stimulation of HCN2current. JMol Cell Cardiol.2012.52(6):1233-1239.
[165] Torrance, N., Smith, B.H., Bennett, M.I., et al. The epidemiology of chronic pain ofpredominantly neuropathic origin. Results from a general population survey. J Pain.2006.7(4):281-289.
[166] Bouhassira, D., Lanteri-Minet, M., Attal, N., et al. Prevalence of chronic pain withneuropathic characteristics in the general population. Pain.2008.136(3):380-387.
[167] Schmidt, R., Kleggetveit, I.P., Namer, B., et al. Double spikes to single electricalstimulation correlates to spontaneous activity of nociceptors in painful neuropathypatients. Pain.2012.153(2):391-398.
[168] Liu, M. and Wood, J.N. The roles of sodium channels in nociception: implicationsfor mechanisms of neuropathic pain. Pain Med.2011.12Suppl3: S93-99.
[169] Pexton, T., Moeller-Bertram, T., Schilling, J.M., et al. Targeting voltage-gatedcalcium channels for the treatment of neuropathic pain: a review of drugdevelopment. Expert Opin Investig Drugs.2011.20(9):1277-1284.
[170] Takeda, M., Tsuboi, Y., Kitagawa, J., et al. Potassium channels as a potentialtherapeutic target for trigeminal neuropathic and inflammatory pain. Mol Pain.2011.7:5.
[171] Nassar, M.A., Baker, M.D., Levato, A., et al. Nerve injury induces robust allodyniaand ectopic discharges in Nav1.3null mutant mice. Mol Pain.2006.2:33.
[172] Hains, B.C., Saab, C.Y., and Waxman, S.G. Changes in electrophysiologicalproperties and sodium channel Nav1.3expression in thalamic neurons after spinalcord injury. Brain.2005.128(Pt10):2359-2371.
[173] Diatchenko, L., Nackley, A.G., Tchivileva, I.E., et al. Genetic architecture of humanpain perception. Trends Genet.2007.23(12):605-613.
[174] Thakor, D.K., Lin, A., Matsuka, Y., et al. Increased peripheral nerve excitability andlocal NaV1.8mRNA up-regulation in painful neuropathy. Mol Pain.2009.5:14.
[175] Altier, C., Dale, C.S., Kisilevsky, A.E., et al. Differential role of N-type calciumchannel splice isoforms in pain. J Neurosci.2007.27(24):6363-6373.
[176] Dogrul, A., Yesilyurt, O., Isimer, A., et al. L-type and T-type calcium channelblockade potentiate the analgesic effects of morphine and selective mu opioidagonist, but not to selective delta and kappa agonist at the level of the spinal cordin mice. Pain.2001.93(1):61-68.
[177] Cheong, E., Lee, S., Choi, B.J., et al. Tuning thalamic firing modes via simultaneousmodulation of T-and L-type Ca2+channels controls pain sensory gating in thethalamus. J Neurosci.2008.28(49):13331-13340.
[178] Matsuyoshi, H., Masuda, N., Chancellor, M.B., et al. Expression ofhyperpolarization-activated cyclic nucleotide-gated cation channels in rat dorsalroot ganglion neurons innervating urinary bladder. Brain Res.2006.1119(1):115-123.
[179] Omana-Zapata, I. and Bley, K.R. A stable prostacyclin analog enhances ectopicactivity in rat sensory neurons following neuropathic injury. Brain Res.2001.904(1):85-92.
[180] Baruscotti, M. and Difrancesco, D. Pacemaker channels. Ann N Y Acad Sci.2004.1015:111-121.
[181] Biel, M., Wahl-Schott, C., Michalakis, S., et al. Hyperpolarization-activated cationchannels: from genes to function. Physiol Rev.2009.89(3):847-885.
[182] Takasu, K., Ono, H., and Tanabe, M. Spinal hyperpolarization-activated cyclicnucleotide-gated cation channels at primary afferent terminals contribute tochronic pain. Pain.2010.151(1):87-96.
[183] Koncz, I., Szel, T., Jaeger, K., et al. Selective pharmacological inhibition of thepacemaker channel isoforms (HCN1-4) as new possible therapeutical targets. CurrMed Chem.2011.18(24):3662-3674.
[184] Song, Y., Li, H.M., Xie, R.G., et al. Evoked bursting in injured Abeta dorsal rootganglion neurons: a mechanism underlying tactile allodynia. Pain.2012.153(3):657-665.
[185] Hatch, R.J., Jennings, E.A., and Ivanusic, J.J. Peripheral hyperpolarization-activatedcyclic nucleotide-gated channels contribute to inflammation-inducedhypersensitivity of the rat temporomandibular joint. Eur J Pain.2012.
[186] Emery, E.C., Young, G.T., and Mcnaughton, P.A. HCN2ion channels: an emergingrole as the pacemakers of pain. Trends Pharmacol Sci.2012.33(8):456-463.
[187] Decosterd, I. and Woolf, C.J. Spared nerve injury: an animal model of persistentperipheral neuropathic pain. Pain.2000.87(2):149-158.
[188] Vasilyev, D.V., Shan, Q., Lee, Y., et al. Direct inhibition of Ih by analgesicloperamide in rat DRG neurons. J Neurophysiol.2007.97(5):3713-3721.
[189] Djouhri, L., Fang, X., Koutsikou, S., et al. Partial nerve injury induceselectrophysiological changes in conducting (uninjured) nociceptive andnonnociceptive DRG neurons: Possible relationships to aspects of peripheralneuropathic pain and paresthesias. Pain.2012.153(9):1824-1836.
[190] Chaplan, S.R., Guo, H.Q., Lee, D.H., et al. Neuronal hyperpolarization-activatedpacemaker channels drive neuropathic pain. J Neurosci.2003.23(4):1169-1178.
[191] Yao, H., Donnelly, D.F., Ma, C., et al. Upregulation of thehyperpolarization-activated cation current after chronic compression of the dorsalroot ganglion. J Neurosci.2003.23(6):2069-2074.
[192] Kitagawa, J., Takeda, M., Suzuki, I., et al. Mechanisms involved in modulation oftrigeminal primary afferent activity in rats with peripheral mononeuropathy. Eur JNeurosci.2006.24(7):1976-1986.
[193] Jiang, Y.Q., Xing, G.G., Wang, S.L., et al. Axonal accumulation ofhyperpolarization-activated cyclic nucleotide-gated cation channels contributes tomechanical allodynia after peripheral nerve injury in rat. Pain.2008.137(3):495-506.
[194] Papp, I., Hollo, K., and Antal, M. Plasticity of hyperpolarization-activated andcyclic nucleotid-gated cation channel subunit2expression in the spinal dorsal hornin inflammatory pain. Eur J Neurosci.2010.32(7):1193-1201.
[195] Kajander, K.C. and Bennett, G.J. Onset of a painful peripheral neuropathy in rat: apartial and differential deafferentation and spontaneous discharge in A beta and Adelta primary afferent neurons. J Neurophysiol.1992.68(3):734-744.
[196] Liu, C.N., Wall, P.D., Ben-Dor, E., et al. Tactile allodynia in the absence of C-fiberactivation: altered firing properties of DRG neurons following spinal nerve injury.Pain.2000.85(3):503-521.
[197] Acosta, C., Mcmullan, S., Djouhri, L., et al. HCN1and HCN2in Rat DRG neurons:levels in nociceptors and non-nociceptors, NT3-dependence and influence ofCFA-induced skin inflammation on HCN2and NT3expression. PLoS One.2012.7(12): e50442.
[198] Jolly, M. Association of rheumatologic disease with preeclampsia. Obstet Gynecol.2004.104(5Pt1):1105-1106; author reply1106.
[199] Ma, C. and Lamotte, R.H. Multiple sites for generation of ectopic spontaneousactivity in neurons of the chronically compressed dorsal root ganglion. J Neurosci.2007.27(51):14059-14068.
[200] Devor, M. Ectopic discharge in Abeta afferents as a source of neuropathic pain. ExpBrain Res.2009.196(1):115-128.
[201] Tu, H., Deng, L., Sun, Q., et al. Hyperpolarization-activated, cyclic nucleotide-gatedcation channels: roles in the differential electrophysiological properties of ratprimary afferent neurons. J Neurosci Res.2004.76(5):713-722.
[202] Zhu, Y.F. and Henry, J.L. Excitability of Abeta sensory neurons is altered in ananimal model of peripheral neuropathy. BMC Neurosci.2012.13:15.
[203] Scheindlin, S. Ephedra: once a boon, now a bane. Mol Interv.2003.3(7):358-360.
[204] Charlton, S.T., Davis, S.S., and Illum, L. Evaluation of effect of ephedrine on thetransport of drugs from the nasal cavity to the systemic circulation and the centralnervous system. J Drug Target.2007.15(5):370-377.
[205] Langendijk, P.N. and Wilde, A.A.[Medication for ADHD and the risk ofcardiovascular mortality]. Ned Tijdschr Geneeskd.2006.150(31):1713-1714.
[206] Howden, R., Hanlon, P.R., Petranka, J.G., et al. Ephedrine plus caffeine causesage-dependent cardiovascular responses in Fischer344rats. Am J Physiol HeartCirc Physiol.2005.288(5): H2219-2224.
[207] Waluga, M., Janusz, M., Karpel, E., et al. Cardiovascular effects of ephedrine,caffeine and yohimbine measured by thoracic electrical bioimpedance in obesewomen. Clin Physiol.1998.18(1):69-76.
[208] Torpy, J.M., Lynm, C., and Glass, R.M. JAMA patient page. Ephedra and ephedrine.Jama.2003.289(12):1590.
[209] Adamson, P.B., Suarez, J., Ellis, E., et al. Ephedrine increases ventriculararrhythmias in conscious dogs after myocardial infarction. J Am Coll Cardiol.2004.44(8):1675-1678.
[210] Rosenbaum, T. and Gordon, S.E. Quickening the pace: looking into the heart ofHCN channels. Neuron.2004.42(2):193-196.
[211] Hung, Y.C., Kau, Y.C., Zizza, A.M., et al. Ephedrine blocks rat sciatic nerve in vivoand sodium channels in vitro. Anesthesiology.2005.103(6):1246-1252.
[212] Barbuti, A., Baruscotti, M., Altomare, C., et al. Action of internal pronase on thef-channel kinetics in the rabbit SA node. J Physiol.1999.520Pt3:737-744.
[213] Ishii, T.M., Takano, M., Xie, L.H., et al. Molecular characterization of thehyperpolarization-activated cation channel in rabbit heart sinoatrial node. J BiolChem.1999.274(18):12835-12839.
[214] Moroni, A., Barbuti, A., Altomare, C., et al. Kinetic and ionic properties of thehuman HCN2pacemaker channel. Pflugers Arch.2000.439(5):618-626.