成年豚鼠膀胱ICC上超极化激活环核苷酸门控通道（HCN）电生理的初步研究
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摘要
众所周知,膀胱肌组织能够产生不受神经系统控制的自发性动作电位,但目前其机制尚未明了。前期的研究中已经证实了膀胱存在ICC,简单记录了Ih电流。这些结果都不能证实ICC在膀胱中到底起到何种作用。
Ih电流(在心脏称为If电流)在胃肠道和心脏窦房结的研究中被认为是“起搏电流”,而HCN通道是Ih电流的分子基础。我们前期的系列研究中已经提示ICC上可能存在HCN通道,但是其电生理特征还尚未明确。同时,既往的实验方法中采用培养的ICC进行电生理实验,效果并不理想,其主要原因是培养后的ICC进行膜片钳实验时难度很大,而且其所测参数并不一定代表了真实生理状态下的情况。
因此本实验的目的:建立一套稳定、可靠的急性分离方法以获得活性更好的ICC;观察ICC上HCN通道的表达,完善HCN通道基本的电生理参数,为进一步的研究提供实验基础和理论依据。
主要实验结果与结论如下:
1.建立了稳定可靠的急性分离方法,所得到的细胞经免疫组织化学实验方法确认是ICC;其酶消化方案为:Ⅱ型胶原蛋白酶2.0mg/ml,胰酶抑制剂2.0mg/ml,木瓜蛋白酶1.0mg/ml,BSA1.0mg/ml,其消化时间15min。
2.采用c-Kit和HCN抗原的免疫荧光双标法,证明了c-Kit阳性的ICC细胞上具有HCN通道抗原的阳性表达。
3.ICC上记录到了Ih电流,其激活电压位于-140mV～－90mV之间,电流幅度为300-800pA,具有电压依赖性,并能被ZD7288(20μM)和Cs～＋(500μM)阻断。
4.Ih电流反转电位42±2mV,PNa/P_K为0.42,膜电容为10-40pF;胞外ZD7288阻断Ih电流具有浓度依赖性,其IC50为24.7±6.5μmol/L,且其阻断效应不可逆;胞外Cs~+阻断Ih电流具有浓度依赖性,其IC50为232.5±24.8μmol/L,且其阻断效应可逆。
5.胞外钠钾对HCN通道皆有影响,具有浓度依赖性,其浓度的改变会影响HCN通道的激活和电导;胞外给予TTX、TEA及Ba~(2+)对Ih电流无明显影响。
6.胞外钙可明显影响HCN通道的激活时间,具有浓度依赖性;胞内cAMP可影响HCN通道的激活时间,具有浓度依赖性。
As we all know that spontaneous action potential(AP) can be recorded from muscular tissue of bladder, even if its nerval control is removed. But till now its mechanism is unknown to us.It has been confirmed the existence of the ICC in bladder on early study. The Ih current was recorded so simply. All of these results could not confirm which kind of role the ICC may play on functions.
The Ih current is regarded as "pacemaker current" on the study of gastrointestinal tract and sinus node. HCN channels are the molecular basis of the Ih current. Our series of preliminary studies have prompted the existence of HCN channels on ICC in bladder. However, its electrophysiological characteristics have not yet been clear. Additionally, the method of using cultured ICCs was unsatisfactory in electrophysiological experiments. For the most main reason, It's very difficult to clamp patch on cultured ICCs. The test parameters could not meet the actual that is under physiological conditions.
So the aim of our study: To find the method to get better ICCs by acute separation.To observe the expression of HCN by by c-Kit and HCN antigen using double-labeled immunofluorescence (IF). To get the basic electrophysiologic parameters of HCN. To provide the theoretical basis and experimental basis in further research.
Main results and conclusions:
1. We have got the stable and reliable method for better ICCs by acute separation. The Program for its enzymatic digestion:ⅡCollagenase 2.0mg/ml; Trypsin inhibitor 2.0mg/ml ;Papain 1.0mg/ml; BSA 1.0mg/ml. The time of digestion is 15 min.
2. We have confirmed the existence of HCN by c-Kit and HCN antigen using double-labeled immunofluorescence (IF).
3. Whole-cell patch clamp recorded a inward current which began to slowly active between -90mV～-140mV in voltage and time dependent manner without deactivation. The current range is 300-800pA. Ih current were blocked by 20μM ZD7288 and 500uM Cs~+.
4. The reversal potential of Ih was 42±2mV, Na+ versus K+(PNa/PK) was 0.42, and membrane capacitance was 10-40pF. The extracellular ZD7288 blocked Ih current with concentration-dependent, and its IC50 was 24.7±6.5uM. the blocking effect of ZD7288 is not reversible. The extracellular Cs~+ blocked Ih current with concentration-dependent, and its IC50 was 232.5±24.8μM. the blocking effect of Cs~+ is reversible.
5. Both the extracellular Na~+ and K~+ could impact activation and conductance of HCN with concentration-dependent. There were no significant effect on Ih current by adding extracellular drug such as TTX, TEA, and Ba~(2+).
6. The extracellular Ca2+ could significantly affect the activation time of HCN with concentration-dependent. The intracellular cAMP could significantly affect the activation time of HCN with concentration-dependent.
Ih电流(在心脏称为If电流)在胃肠道和心脏窦房结的研究中被认为是“起搏电流”,而HCN通道是Ih电流的分子基础。我们前期的系列研究中已经提示ICC上可能存在HCN通道,但是其电生理特征还尚未明确。同时,既往的实验方法中采用培养的ICC进行电生理实验,效果并不理想,其主要原因是培养后的ICC进行膜片钳实验时难度很大,而且其所测参数并不一定代表了真实生理状态下的情况。
因此本实验的目的:建立一套稳定、可靠的急性分离方法以获得活性更好的ICC;观察ICC上HCN通道的表达,完善HCN通道基本的电生理参数,为进一步的研究提供实验基础和理论依据。
主要实验结果与结论如下:
1.建立了稳定可靠的急性分离方法,所得到的细胞经免疫组织化学实验方法确认是ICC;其酶消化方案为:Ⅱ型胶原蛋白酶2.0mg/ml,胰酶抑制剂2.0mg/ml,木瓜蛋白酶1.0mg/ml,BSA1.0mg/ml,其消化时间15min。
2.采用c-Kit和HCN抗原的免疫荧光双标法,证明了c-Kit阳性的ICC细胞上具有HCN通道抗原的阳性表达。
3.ICC上记录到了Ih电流,其激活电压位于-140mV～－90mV之间,电流幅度为300-800pA,具有电压依赖性,并能被ZD7288(20μM)和Cs～＋(500μM)阻断。
4.Ih电流反转电位42±2mV,PNa/P_K为0.42,膜电容为10-40pF;胞外ZD7288阻断Ih电流具有浓度依赖性,其IC50为24.7±6.5μmol/L,且其阻断效应不可逆;胞外Cs~+阻断Ih电流具有浓度依赖性,其IC50为232.5±24.8μmol/L,且其阻断效应可逆。
5.胞外钠钾对HCN通道皆有影响,具有浓度依赖性,其浓度的改变会影响HCN通道的激活和电导;胞外给予TTX、TEA及Ba~(2+)对Ih电流无明显影响。
6.胞外钙可明显影响HCN通道的激活时间,具有浓度依赖性;胞内cAMP可影响HCN通道的激活时间,具有浓度依赖性。
As we all know that spontaneous action potential(AP) can be recorded from muscular tissue of bladder, even if its nerval control is removed. But till now its mechanism is unknown to us.It has been confirmed the existence of the ICC in bladder on early study. The Ih current was recorded so simply. All of these results could not confirm which kind of role the ICC may play on functions.
The Ih current is regarded as "pacemaker current" on the study of gastrointestinal tract and sinus node. HCN channels are the molecular basis of the Ih current. Our series of preliminary studies have prompted the existence of HCN channels on ICC in bladder. However, its electrophysiological characteristics have not yet been clear. Additionally, the method of using cultured ICCs was unsatisfactory in electrophysiological experiments. For the most main reason, It's very difficult to clamp patch on cultured ICCs. The test parameters could not meet the actual that is under physiological conditions.
So the aim of our study: To find the method to get better ICCs by acute separation.To observe the expression of HCN by by c-Kit and HCN antigen using double-labeled immunofluorescence (IF). To get the basic electrophysiologic parameters of HCN. To provide the theoretical basis and experimental basis in further research.
Main results and conclusions:
1. We have got the stable and reliable method for better ICCs by acute separation. The Program for its enzymatic digestion:ⅡCollagenase 2.0mg/ml; Trypsin inhibitor 2.0mg/ml ;Papain 1.0mg/ml; BSA 1.0mg/ml. The time of digestion is 15 min.
2. We have confirmed the existence of HCN by c-Kit and HCN antigen using double-labeled immunofluorescence (IF).
3. Whole-cell patch clamp recorded a inward current which began to slowly active between -90mV～-140mV in voltage and time dependent manner without deactivation. The current range is 300-800pA. Ih current were blocked by 20μM ZD7288 and 500uM Cs~+.
4. The reversal potential of Ih was 42±2mV, Na+ versus K+(PNa/PK) was 0.42, and membrane capacitance was 10-40pF. The extracellular ZD7288 blocked Ih current with concentration-dependent, and its IC50 was 24.7±6.5uM. the blocking effect of ZD7288 is not reversible. The extracellular Cs~+ blocked Ih current with concentration-dependent, and its IC50 was 232.5±24.8μM. the blocking effect of Cs~+ is reversible.
5. Both the extracellular Na~+ and K~+ could impact activation and conductance of HCN with concentration-dependent. There were no significant effect on Ih current by adding extracellular drug such as TTX, TEA, and Ba~(2+).
6. The extracellular Ca2+ could significantly affect the activation time of HCN with concentration-dependent. The intracellular cAMP could significantly affect the activation time of HCN with concentration-dependent.
引文
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1.Maeda H,Yamagata A. Requirement of c-kit for development of intestinal pacemaker system [J]. Development, 1992,116(2) :369-375.
2.Komuro T. Anti-c-kit protein immunoreactive cells corresponding to the interstitial cells of Cajal in the guinea-pig small intestine [J]. J Auton Nerv Syst,1996,61(2) :169-174.
3.Sanders KM.Ordog T. Development and plasticity of interstitial cells of Cajal [J].Neurogastroenterol Motil ,1999 ,11 (5) :311-338.
4.Metzger R, Neugebauer A, Rolle U, et al. C-Kit receptor (CD117) in the porcine urinary tract [J]. Pediatr Surg Int. 2008;24(1):67-76.
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6. Huizinga JD,Robinson TL. The search for the origin of rhythmicity in intestinal contraction [J]. Neurogastroenterol Motil,2000,12(1):3-9.
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8. Ishikawa K,Komuro T,Hirota S,et al. Ultrastructural identification of the c-kit-express ing interstial cells in the rat stomach:a comparision of control and Ws/Ws mutant rats [J]. Cell Tissue Res, 1997,289:137-143.
9. SuzukiH.Cellular mechanisms of myogenic activity in gastric smooth muscle [J].Jpn J Physiol,2000,50(3):289-301.
10. Lang RJ, Tonta MA, Zoltkowski BZ, et al. Pyeloureteric peristalsis: role of atypical smooth muscle cells and interstitial cells of Cajal-like cells as pacemakers [J]. J Physiol. 2006;576(Pt 3):695-705.
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31. Chesnoy-Marchais D. Characterization of a chloride conductance activated by hyper -polarization in Aplysia neurones [J]. J Physiol, 1983,342:277-308.
32. Chesnoy-Marchais D, Evans MG. Chloride channels activated by hyperpolarization in Aplysia neurones [J]. Pflugers Arch, 1986,407(6):694-6.
33. Champigny G, Lenfant J. Block and activation of the hyperpolarization-activated inward current by Ba and Cs in frog sinus venosus [J]. Pflugers Arch, 1986,407(6):684-90.
34. Champigny G, Bois P, Lenfant J. Characterization of the ionic mechanism responsible for the hyperpolarization-activated current in frog sinus venosus [J]. Pflugers Arch, 1987,410(1-2): 159-64.
35. DiFrancesco D, Tromba C. Inhibition of the hyperpolarization-activated current (if) induced by acetylcholine in rabbit sino-atrial node myocytes [J]. J Physiol, 1988,405:477-91.
36. Edman A, Grampp W. Ion permeation through hyperpolarization-activated membrane channels (Q-channels) in the lobster stretch receptor neurone [J]. Pflugers Arch. 1989,413(3):249-55.
37. Santoro B, Liu DT, Yao H, et al. Identification of a gene encoding a hyperpolarization -activated pacemaker channel of brain [J]. Cell. 1998;93(5):717-29.
38. Santoro B, Tibbs GR. The HCN gene family: molecular basis of the hyperpolarization -activated pacemaker channels [J]. Ann N YAcad Sci. 1999;868:741-64. Review.
39. Angstadt JD, Calabrese RL. A hyperpolarization-activated inward current in heart interneurons of the medicinal leech [J]. J Neurosci, 1989,9(8):2846-57.
40. Tokimasa T, Akasu T. Cyclic AMP regulates an inward rectifying sodium-potassium current in dissociated bull-frog sympathetic neurones [J]. J Physiol, 1990,420:409-29.
41. Coleman HA, Parkington HC. Hyperpolarization-activated channels in myometrium: a patch clamp study [J]. Prog Clin Biol Res. 1990;327:665-72.
42. Yatani A, Brown AM. Regulation of cardiac pacemaker current If in excised membranes from sinoatrial node cells [J]. Am J Physiol, 1990,258: 1947-51.
43. Denyer JC, Brown HF. Pacemaking in rabbit isolated sino-atrial node cells during Cs+ block of the hyperpolarization-activated current if [J]. J Physiol, 1990,429:401-9.
44. Hisada T, Ordway RW, Kirber MT, et al. Hyperpolarization-activated cationic channels in smooth muscle cells are stretch sensitive [J]. Pflugers Arch. 1991,417(5):493-9.
45. Van Ginneken AC, Giles W. Voltage clamp measurements of the hyperpolarization -activated inward current I(f) in single cells from rabbit sino-atrial node [J]. J Physiol, 1991,434:57-83.
46. Satoh H, Sperelakis N. Identification of the hyperpolarization-activated inward current in young embryonic chick heart myocytes [J]. J Dev Physiol, 1991,15(4):247-52.
47. Frace AM, Maruoka F, Noma A. External K+ increases Na+ conductance of the hyperpolarization-activated current in rabbit cardiac pacemaker cells [J]. Pflugers Arch, 1992,421(2-3):97-9.
48. Schachtman DP, Schroeder JI, Lucas WJ, et al. Expression of an inward-rectifying potassium channel by the Arabidopsis KATl cDNA [J]. Science. 1992, 4;258:1654-8.
49. Wang XJ, Golomb D, Rinzel J. et al. Emergent spindle oscillations and intermittent burst firing in a thalamic model: specific neuronal mechanisms [J]. Proc Natl Acad Sci. 1995, 92(12):5577-81.
50. Pedarzani P, Storm JF. Protein kinase A-independent modulation of ion channels in the brain by cyclic AMP [J]. Proc Natl Acad Sci. 1995;92(25): 11716-20.
51. Zaza A, Rocchetti M, DiFrancesco D. Modulation of the hyperpolarization-activated current (I(f)) by adenosine in rabbit sinoatrial myocytes [J]. Circulation. 1996, 94(4):734_41.
52. Cerbai E, Pino R, Porciatti F, et al. Characterization of the hyperpolarization-activated current, I(f), in ventricular myocytes from human failing heart [J]. Circulation. 1997;95(3):568-71.
53. Gauss R, Seifert R, Kaupp UB. Molecular identification of a hyperpolarization -activated channel in sea urchin sperm [J]. Nature.1998,393: 583-587.
54. Luthi A, Mccormick DA. H-current: Properties of a Neuronal and Network Pacemaker [J]. Neurons,1998, 21(1): 9-12.
55. Vaccari T, Moroni A, Rocchi M, et al. The human gene coding for HCN2, a pacemaker channel of the heart [J]. Biochim Biophys Acta. 1999,1446(3):419-25.
56. Richter H, Heinemann U, Eder C. Hyperpolarization-activated cation currents in stellate and pyramidal neurons of rat entorhinal cortex [J]. Neurosci Lett. 2000; 281(1):33-6.
57. Southan AP, Morris NP, Stephens GJ, et al. Hyperpolarization-activated currents in presynaptic terminals of mouse cerebellar basket cells [J]. J Physiol. 2000;526 Pt 1:91-7
58. Beaumont V, Zucker RS. Enhancement of Synaptic Transmission by Cyclic AMP Modulation of Presynaptic Ih Channels [J]. Nat Neurosci, 2000, 3 (2): 133-141.
59. Yu H, Wu J, Potapova l,et al. MinK-related peptide 1: A beta subunit for the HCN ion channel subunit family enhances expression and speeds activation [J]. Circ Res. 2001;88(12):E84-7.
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63. Zhao Y, Scheuer T, Catterall WA. Reversed voltage-dependent gating of a bacterial sodium channel with proline substitutions in the S6 transmembrane segment [J]. Proc Natl Acad Sci. 2004;101(51):17873-8.\
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1.Yanagihara K, Noma A, Irisawa H. Reconstruction of sino-atrial node pacemaker potential based on the voltage clamp experiments [J]. Jp-J Physiol, 1980,30(6):841-57.
2.Hart G. The kinetics and temperature dependence of the pace-maker current if in sheep Purkinje fibres [J]. J Physiol, 1983,337:401-16.
3.Chesnoy-Marchais D. Characterization of a chloride conductance activated by hyper -polarization in Aplysia neurones [J]. J Physiol, 1983,342:277-308.
4.Chesnoy-Marchais D, Evans MG. Chloride channels activated by hyperpolarization in Aplysia neurones [J]. Pflugers Arch, 1986,407(6):694-6.
5.Champigny G, Lenfant J. Block and activation of the hyperpolarization-activated inward current by Ba and Cs in frog sinus venosus [J]. Pflugers Arch,1986,407(6):684-90.
6.Champigny G, Bois P, Lenfant J. Characterization of the ionic mechanism responsible for the hyperpolarization-activated current in frog sinus venosus [J]. Pflugers Arch, 1987,410(1-2): 159-64.
7. DiFrancesco D, Tromba C. Inhibition of the hyperpolarization-activated current (if) induced by acetylcholine in rabbit sino-atrial node myocytes [J]. J Physiol, 1988,405:477-91.
8. Edman A, Grampp W. Ion permeation through hyperpolarization-activated membrane channels (Q-channels) in the lobster stretch receptor neurone [J]. Pflugers Arch. 1989,413(3):249-55.
9. Angstadt JD, Calabrese RL. A hyperpolarization-activated inward current in heart interneurons of the medicinal leech [J]. J Neurosci, 1989,9(8):2846-57.
10. Tokimasa T, Akasu T. Cyclic AMP regulates an inward rectifying sodium-potassium current in dissociated bull-frog sympathetic neurones [J]. J Physiol, 1990,420:409-29.
11. Coleman HA, Parkington HC. Hyperpolarization-activated channels in myometrium: a patch clamp study [J]. Prog Clin Biol Res. 1990;327:665-72.
12. Yatani A, Brown AM. Regulation of cardiac pacemaker current If in excised membranes from sinoatrial node cells [J]. Am J Physiol, 1990,258: 1947-51.
13. Denyer JC, Brown HE Pacemaking in rabbit isolated sino-atrial node cells during Cs+ block of the hyperpolarization-activated current if [J]. J Physiol, 1990,429:401-9.
14. Hisada T, Ordway RW, Kirber MT, et al. Hyperpolarization-activated cationic channels in smooth muscle cells are stretch sensitive [J]. Pflugers Arch. 1991,417(5):493-9.
15. Van Ginneken AC, Giles W. Voltage clamp measurements of the hyperpolarization -activated inward current I(f) in single cells from rabbit sino-atrial node [J]. J Physiol, 1991,434:57-83.
16. Satoh H, Sperelakis N. Identification of the hyperpolarization-activated inward current in young embryonic chick heart myocytes [J]. J Dev Physiol, 1991,15(4):247-52.
17. Frace AM, Maruoka F, Noma A. External K+ increases Na+ conductance of the hyperpolarization-activated current in rabbit cardiac pacemaker cells [J]. Pflugers Arch, 1992,421(2-3):97-9.
18. Schachtman DP, Schroeder JI, Lucas WJ, et al. Expression of an inward-rectifying potassium channel by the Arabidopsis KAT1 cDNA [J]. Science. 1992, 4;258:1654-8.
19. Wang XJ, Golomb D, Rinzel J. et al. Emergent spindle oscillations and intermittent burst firing in a thalamic model: specific neuronal mechanisms [J]. Proc Natl Acad Sci 1995,92(12):5577-81.
20. Pedarzani P, Storm JF. Protein kinase A-independent modulation of ion channels in the brain by cyclic AMP [J]. Proc Natl Acad Sci. 1995;92(25): 11716-20.
21. Zaza A, Rocchetti M, DiFrancesco D. Modulation of the hyperpolarization-activated current (I(f)) by adenosine in rabbit sinoatrial myocytes [J]. Circulation. 1996, 94(4):734_41.
22. Cerbai E, Pino R, Porciatti F, et al. Characterization of the hyperpolarization-activated current, I(f), in ventricular myocytes from human failing heart [J]. Circulation. 1997;95(3):568-71.
23. Gauss R, Seifert R, Kaupp UB. Molecular identification of a hyperpolarization -activated channel in sea urchin sperm [J]. Nature. 1998,393: 583-587.
24. Santoro B, Liu DT, Yao H, et al. Identification of a gene encoding a hyperpolarization -activated pacemaker channel of brain [J]. Cell. 1998;93(5):717-29.
25. Santoro B, Tibbs GR. The HCN gene family: molecular basis of the hyperpolarization -activated pacemaker channels [J]. Ann N YAcad Sci. 1999;868:741-64. Review.
26. Luthi A, Mccormick DA. H-current : Properties of a Neuronal and Network Pacemaker [J]. Neurons, 1998, 21(1): 9-12.
27. Vaccari T, Moroni A, Rocchi M, et al. The human gene coding for HCN2, a pacemaker channel of the heart [J]. Biochim Biophys Acta. 1999,1446(3):419-25.
28. Richter H, Heinemann U, Eder C. Hyperpolarization-activated cation currents in stellate and pyramidal neurons of rat entorhinal cortex [J]. Neurosci Lett. 2000; 281(1):33-6.
29. Southan AP, Morris NP, Stephens GJ, et al. Hyperpolarization-activated currents in presynaptic terminals of mouse cerebellar basket cells [J]. J Physiol. 2000;526 Pt 1:91-7.
30. Beaumont V, Zucker RS. Enhancement of Synaptic Transmission by Cyclic AMP Modulation of Presynaptic Ih Channels [J]. Nat Neurosci, 2000, 3 (2): 133-141.
31. Yu H, Wu J, Potapova I,et al. MinK-related peptide 1: A beta subunit for the HCN ion channel subunit family enhances expression and speeds activation [J]. Circ Res. 2001;88(12):E84-7.
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