氯离子转运体KCC2/NKCC1参与病理性疼痛的研究进展
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摘要
<正>阳离子氯离子联合转运蛋白(cation-Cl-cotransporter,CCC)是一组转运Na~+、K~+、Cl~-进出细胞的膜蛋白。其中,钾氯联合转运蛋白2(K~+-Cl~- cotransporter 2,KCC2)和钠钾氯联合转运蛋白1(Na~+-K~+-Cl~- cotransporter 1,NKCC1)是调节神经系统氯离子稳态的主要CCC,NKCC1将Cl~-转运入胞内,KCC2将Cl~-转运至胞外,两者共同调节氯离子平衡及
引文
[1] Yousuf MS,Kerr BJ. The role of regulatory transporters in neuropathic pain[J]. Adv Pharmacol,2016,75:245-271.
[2]Payne JA,Stevenson TJ,Donaldson LF. Molecular characterization of a putative K-Cl cotransporter in rat brain. A neuronal-specific isoform[J]. J Biol Chem,1996,271:16245-16252.
[3]Sallinen R,Tornberg J,Putkiranta M,et al. Chromosomal localization of SLC12A5/Slc12a5,the human and mouse genes for the neuron-specific K(+)-Cl(-)cotransporter(KCC2)defines a new region of conserved homology[J]. Cytogenet Cell Genet,2001,94:67-70.
[4]Warmuth S,Zimmermann I,Dutzler R. X-ray structure of the C-terminal domain of a prokaryotic cation-chloride cotransporter[J].Structure,2009,17:538-546.
[5]D9ding A,Hartmann AM,Beyer T,et al. KCC2 transport activity requires the highly conserved L675in the C-terminalβ1 strand[J].Biochem Biophys Res Commun,2012,420:492-497.
[6]Markkanen M,Ludwig A,Khirug S,et al. Implications of the Nterminal heterogeneity for the neuronal K-Cl cotransporter KCC2function[J]. Brain Res,2017,1675:87-101.
[7]Uvarov P,Ludwig A,Markkanen M,et al. Coexpression and heteromerization of two neuronal K-Cl cotransporter isoforms in neonatal brain[J]. J Biol Chem,2009,284:13696-13704.
[8]De LHP,Kahle KT,Rinehart J,et al. WNK3 bypasses the tonicity requirement for K-Cl cotransporter activation via a phosphatasedependent pathway[J]. Proc Natl Acad Sci USA,2006,103:1976-1981.
[9]Jalali R,Lodder H,Zandiehdoulabi B,et al. The Role of Na:K:2Cl Cotransporter 1(NKCC1/SLC12A2)in Dental Epithelium during Enamel Formation in Mice[J]. Front Physiol,2017,8:924.
[10]Lee HA,Hong SH,Kim JW,et al. Possible involvement of DNA methylation in NKCC1 gene expression during postnatal development and in response to ischemia[J]. J Neurochem,2010,114:520-529.
[11]Price TJ,Hargreaves KM,Cervero F. Protein expression and mRNA cellular distribution of the NKCC1 cotransporter in the dorsal root and trigeminal ganglia of the rat[J]. Brain Res,2006,1112:146-158.
[12]Cristo GD,Awad PN,Hamidi S,et al. KCC2,epileptiform synchronization,and epileptic disorders[J]. Prog Neurobiol,2018,162:1-16.
[13] Ben-Ari Y. NKCC1 chloride importer antagonists attenuate many neurological and psychiatric disorders[J]. Trends Neurosci,2017,40:536-554.
[14]Schulte JT,Wierenga CJ,Bruining H. Chloride transporters and GABA polarity in developmental,neurological and psychiatric conditions[J]. Neurosci Biobehav Rev,2018,90:260-271.
[15]Hu D,Yu ZL,Zhang Y,et al. Bumetanide treatment during early development rescues maternal separation-induced susceptibility to stress[J]. Sci Rep,2017,7:11878.
[16] Dzhala VI,Talos DM,Dan AS,et al. NKCC1 transporter facilitates seizures in the developing brain[J]. Nat Med,2005,11:1205-1213.
[17]Shekarabi M,Zhang J,Khanna AR,et al. WNK kinase signaling in ion homeostasis and human disease[J]. Cell Metab,2017,25:285-299.
[18]Buchin A,Chizhov A,Huberfeld G,et al. Reduced efficacy of the KCC2 cotransporter promotes epileptic oscillations in a subiculum network model[J]. J Neurosci,2016,36:11619-11633.
[19]Tyzio R,Nardou R,Ferrari DC,et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring[J]. Science,2014,343:675-679.
[20]Knabl J,Witschi R,H9sl K,et al. Reversal of pathological pain through specific spinal GABAAreceptor subtypes[J]. Nature,2008,451:330-334.
[21] Iura A,Takahashi A,Hakata S,et al. Reductions in tonic GABAergic current in substantia gelatinosa neurons and GABAAreceptorδsubunit expression after chronic constriction injury of the sciatic nerve in mice[J]. Eur J Pain,2016,20:1678-1688.
[22]Mòdol L,Cobianchi S,Navarro X. Prevention of NKCC1 phosphorylation avoids downregulation of KCC2 in central sensory pathways and reduces neuropathic pain after peripheral nerve injury[J].Pain,2014,155:1577-1590.
[23]韩媛媛,黄征,王艳萍,等.氯离子转运体在神经病理性疼痛大鼠背根神经节上表达的研究[J].中国疼痛医学杂志,2016,22:583-590.
[24]朱少飞,唐群新.鞘内注射布美他尼对大鼠急性疼痛行为及钠钾氯联合转运蛋白1表达的影响[J].实用药物与临床,2015,18:272-276.
[25]Laird JM,Garcíanicas E,Delpire EJ,et al. Presynaptic inhibition and spinal pain processing in mice:a possible role of the NKCC1cation-chloride co-transporter in hyperalgesia[J]. Neurosci Lett,2004,361:200-203.
[26] Delpire E,Austin TM. Kinase regulation of Na+-K+-2Cl-cotransport in primary afferent neurons[J]. J Physiol,2010,588:3365-3373.
[27]Pitcher MH,Cervero F. Role of the NKCC1 co-transporter in sensitization of spinal nociceptive neurons[J]. Pain,2010,151:756-762.
[28] Pitcher MH,Nieto FR,Cervero F. Stimulation of cutaneous low threshold mechanoreceptors in mice after intracolonic capsaicin increases spinal c-Fos labeling in an NKCC1-dependent fashion[J].J Pain,2013,14:57-65.
[29]Takazawa T,Choudhury P,Tong CK,et al. Inhibition mediated by glycinergic and GABAergic receptors on excitatory neurons in mouse superficial dorsal horn is location-specific but modified by inflammation[J]. J Neurosci,2017,37:2336-2348.
[30] Iura A,Takahashi A,Hakata S,et al. Reductions in tonic GABAergic current in substantia gelatinosa neurons and GABAAreceptorδsubunit expression after chronic constriction injury of the sciatic nerve in mice[J]. Eur J Pain,2016,20:1678-1688.
[31]Javdani F,HollóK,Hegedüs K,et al. Differential expression patterns of K(+)/Cl(-)cotransporter 2 in neurons within the superficial spinaldorsal horn of rats[J]. J Comp Neurol,2015,523:1967-1983.
[32]Coull JAM,Boudreau D,Bachand K,et al. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain[J]. Nature,2003,424:938-942.
[33]Liu CK,Liao WT,Chu YC,et al. pulsed radiofrequency attenuates complete freund’s adjuvant-induced epigenetic suppression of potassium chloride cotransporter 2 expression[J]. Pain Med,2017,18:807-813.
[34] Lin CR,Cheng JK,Wu CH,et al. Epigenetic suppression of potassium-chloride co-transporter 2 expression in inflammatory pain induced by complete Freund’s adjuvant(CFA)[J]. Eur J Pain,2016,21:309-321.
[35]Zhang J,Yu J,Kannampalli P,et al. MicroRNA-mediated downregulation of potassium-chloride-cotransporter and vesicularγ-aminobutyric acid transporter expression in spinal cord contributes to neonatal cystitis-induced visceral pain in rats[J]. Pain,2017,158:2461-2474.
[36]贾晓明,杨建平,王丽娜,等.骨癌痛大鼠脊髓背角KCC2的表达及可能机制[J].中国药理学通报,2010,26:1463-1466.
[37]钱晓波,沈濛溦,高建瓴,等.鞘内注射CLP257对大鼠骨癌痛的影响[J].中华麻醉学杂志,2017,37:88-91.
[38]Kahle KT,Schmouth JF,Lavastre V,et al. Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition[J]. Sci Signal,2016,9:ra32.
[39]Li L,Chen SR,Chen H,et al. Chloride homeostasis critically regulates synaptic NMDA receptor activity in neuropathic pain[J].Cell Rep,2016,15:1376-1383.
[40]Dai S,Qi Y,Fu J,et al. Dexmedetomidine attenuates persistent postsurgical pain by upregulating K+-Cl-cotransporter-2 in the spinal dorsal horn in rats[J]. J Pain Res,2018,11:993-1004.
[41]Ford A,Castonguay A,Cottet M,et al. Engagement of the GABA to KCC2 signaling pathway contributes to the analgesic effects of A3AR agonists in neuropathic pain[J]. J Neurosci,2015,35:6057-6067.
[42]He Y,Ji W,Huang H. Effect of the cation-chloride cotransporter inhibitor furosemide in a rat model of postoperative pain[J]. Pain Med,2011,12:1427-1434.
[43]Zhou HY,Chen SR,Byun HS,et al. N-Methyl-d-aspartate Receptor-and Calpain-mediated Proteolytic Cleavage of K+-Cl-Cotransporter-2 Impairs Spinal Chloride Homeostasis in Neuropathic Pain[J]. J Biol Chem,2012,287:33853-33864.
[44]Miletic G,Miletic V. Loose ligation of the sciatic nerve is associated with TrkB receptor-dependent decreases in KCC2 protein levels in the ipsilateral spinal dorsal horn[J]. Pain,2008,137:532-539.
[45]Rivera C,Li H,Thomas-Crusells J,et al. BDNF-induced Trk B activation down-regulates the K+-Cl-cotransporter KCC2 and impairs neuronal Cl-extrusion[J]. J Cell Biol,2002,159:747-752.
[46]代淑红,孙玉娥,荣辉,等. K252a通过下调脊髓背角钾氯共转运体-2的表达缓解大鼠术后持续性痛[J].国际麻醉学与复苏杂志,2016,37:426-429.
[47] Zhang Z,Wang X,Wang W,et al. Brain-derived neurotrophic factor-mediated downregulation of brainstem K+-Cl-otransporter and cell-type-specific GABA impairment for activation of descending pain facilitation[J]. Mol Pharmacol,2013,84:511-520.
[48]Shih HC,Kuan YH,Shyu BC. Targeting BDNF in the medial thalamus for the treatment of central poststroke pain in a rodent model[J]. Pain,2017,158:1302-1313.
[49]Gagnon M,Bergeron MJ,Lavertu G,et al. Chloride extrusion enhancers as novel therapeutics for neurological diseases[J]. Nat Med,2013,19:1524-1528.
[50]Ferrini F,Lorenzo LE,Godin AG,et al. Enhancing KCC2 function counteracts morphine-induced hyperalgesia[J]. Sci Rep,2017,7:3870.
[2]Payne JA,Stevenson TJ,Donaldson LF. Molecular characterization of a putative K-Cl cotransporter in rat brain. A neuronal-specific isoform[J]. J Biol Chem,1996,271:16245-16252.
[3]Sallinen R,Tornberg J,Putkiranta M,et al. Chromosomal localization of SLC12A5/Slc12a5,the human and mouse genes for the neuron-specific K(+)-Cl(-)cotransporter(KCC2)defines a new region of conserved homology[J]. Cytogenet Cell Genet,2001,94:67-70.
[4]Warmuth S,Zimmermann I,Dutzler R. X-ray structure of the C-terminal domain of a prokaryotic cation-chloride cotransporter[J].Structure,2009,17:538-546.
[5]D9ding A,Hartmann AM,Beyer T,et al. KCC2 transport activity requires the highly conserved L675in the C-terminalβ1 strand[J].Biochem Biophys Res Commun,2012,420:492-497.
[6]Markkanen M,Ludwig A,Khirug S,et al. Implications of the Nterminal heterogeneity for the neuronal K-Cl cotransporter KCC2function[J]. Brain Res,2017,1675:87-101.
[7]Uvarov P,Ludwig A,Markkanen M,et al. Coexpression and heteromerization of two neuronal K-Cl cotransporter isoforms in neonatal brain[J]. J Biol Chem,2009,284:13696-13704.
[8]De LHP,Kahle KT,Rinehart J,et al. WNK3 bypasses the tonicity requirement for K-Cl cotransporter activation via a phosphatasedependent pathway[J]. Proc Natl Acad Sci USA,2006,103:1976-1981.
[9]Jalali R,Lodder H,Zandiehdoulabi B,et al. The Role of Na:K:2Cl Cotransporter 1(NKCC1/SLC12A2)in Dental Epithelium during Enamel Formation in Mice[J]. Front Physiol,2017,8:924.
[10]Lee HA,Hong SH,Kim JW,et al. Possible involvement of DNA methylation in NKCC1 gene expression during postnatal development and in response to ischemia[J]. J Neurochem,2010,114:520-529.
[11]Price TJ,Hargreaves KM,Cervero F. Protein expression and mRNA cellular distribution of the NKCC1 cotransporter in the dorsal root and trigeminal ganglia of the rat[J]. Brain Res,2006,1112:146-158.
[12]Cristo GD,Awad PN,Hamidi S,et al. KCC2,epileptiform synchronization,and epileptic disorders[J]. Prog Neurobiol,2018,162:1-16.
[13] Ben-Ari Y. NKCC1 chloride importer antagonists attenuate many neurological and psychiatric disorders[J]. Trends Neurosci,2017,40:536-554.
[14]Schulte JT,Wierenga CJ,Bruining H. Chloride transporters and GABA polarity in developmental,neurological and psychiatric conditions[J]. Neurosci Biobehav Rev,2018,90:260-271.
[15]Hu D,Yu ZL,Zhang Y,et al. Bumetanide treatment during early development rescues maternal separation-induced susceptibility to stress[J]. Sci Rep,2017,7:11878.
[16] Dzhala VI,Talos DM,Dan AS,et al. NKCC1 transporter facilitates seizures in the developing brain[J]. Nat Med,2005,11:1205-1213.
[17]Shekarabi M,Zhang J,Khanna AR,et al. WNK kinase signaling in ion homeostasis and human disease[J]. Cell Metab,2017,25:285-299.
[18]Buchin A,Chizhov A,Huberfeld G,et al. Reduced efficacy of the KCC2 cotransporter promotes epileptic oscillations in a subiculum network model[J]. J Neurosci,2016,36:11619-11633.
[19]Tyzio R,Nardou R,Ferrari DC,et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring[J]. Science,2014,343:675-679.
[20]Knabl J,Witschi R,H9sl K,et al. Reversal of pathological pain through specific spinal GABAAreceptor subtypes[J]. Nature,2008,451:330-334.
[21] Iura A,Takahashi A,Hakata S,et al. Reductions in tonic GABAergic current in substantia gelatinosa neurons and GABAAreceptorδsubunit expression after chronic constriction injury of the sciatic nerve in mice[J]. Eur J Pain,2016,20:1678-1688.
[22]Mòdol L,Cobianchi S,Navarro X. Prevention of NKCC1 phosphorylation avoids downregulation of KCC2 in central sensory pathways and reduces neuropathic pain after peripheral nerve injury[J].Pain,2014,155:1577-1590.
[23]韩媛媛,黄征,王艳萍,等.氯离子转运体在神经病理性疼痛大鼠背根神经节上表达的研究[J].中国疼痛医学杂志,2016,22:583-590.
[24]朱少飞,唐群新.鞘内注射布美他尼对大鼠急性疼痛行为及钠钾氯联合转运蛋白1表达的影响[J].实用药物与临床,2015,18:272-276.
[25]Laird JM,Garcíanicas E,Delpire EJ,et al. Presynaptic inhibition and spinal pain processing in mice:a possible role of the NKCC1cation-chloride co-transporter in hyperalgesia[J]. Neurosci Lett,2004,361:200-203.
[26] Delpire E,Austin TM. Kinase regulation of Na+-K+-2Cl-cotransport in primary afferent neurons[J]. J Physiol,2010,588:3365-3373.
[27]Pitcher MH,Cervero F. Role of the NKCC1 co-transporter in sensitization of spinal nociceptive neurons[J]. Pain,2010,151:756-762.
[28] Pitcher MH,Nieto FR,Cervero F. Stimulation of cutaneous low threshold mechanoreceptors in mice after intracolonic capsaicin increases spinal c-Fos labeling in an NKCC1-dependent fashion[J].J Pain,2013,14:57-65.
[29]Takazawa T,Choudhury P,Tong CK,et al. Inhibition mediated by glycinergic and GABAergic receptors on excitatory neurons in mouse superficial dorsal horn is location-specific but modified by inflammation[J]. J Neurosci,2017,37:2336-2348.
[30] Iura A,Takahashi A,Hakata S,et al. Reductions in tonic GABAergic current in substantia gelatinosa neurons and GABAAreceptorδsubunit expression after chronic constriction injury of the sciatic nerve in mice[J]. Eur J Pain,2016,20:1678-1688.
[31]Javdani F,HollóK,Hegedüs K,et al. Differential expression patterns of K(+)/Cl(-)cotransporter 2 in neurons within the superficial spinaldorsal horn of rats[J]. J Comp Neurol,2015,523:1967-1983.
[32]Coull JAM,Boudreau D,Bachand K,et al. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain[J]. Nature,2003,424:938-942.
[33]Liu CK,Liao WT,Chu YC,et al. pulsed radiofrequency attenuates complete freund’s adjuvant-induced epigenetic suppression of potassium chloride cotransporter 2 expression[J]. Pain Med,2017,18:807-813.
[34] Lin CR,Cheng JK,Wu CH,et al. Epigenetic suppression of potassium-chloride co-transporter 2 expression in inflammatory pain induced by complete Freund’s adjuvant(CFA)[J]. Eur J Pain,2016,21:309-321.
[35]Zhang J,Yu J,Kannampalli P,et al. MicroRNA-mediated downregulation of potassium-chloride-cotransporter and vesicularγ-aminobutyric acid transporter expression in spinal cord contributes to neonatal cystitis-induced visceral pain in rats[J]. Pain,2017,158:2461-2474.
[36]贾晓明,杨建平,王丽娜,等.骨癌痛大鼠脊髓背角KCC2的表达及可能机制[J].中国药理学通报,2010,26:1463-1466.
[37]钱晓波,沈濛溦,高建瓴,等.鞘内注射CLP257对大鼠骨癌痛的影响[J].中华麻醉学杂志,2017,37:88-91.
[38]Kahle KT,Schmouth JF,Lavastre V,et al. Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition[J]. Sci Signal,2016,9:ra32.
[39]Li L,Chen SR,Chen H,et al. Chloride homeostasis critically regulates synaptic NMDA receptor activity in neuropathic pain[J].Cell Rep,2016,15:1376-1383.
[40]Dai S,Qi Y,Fu J,et al. Dexmedetomidine attenuates persistent postsurgical pain by upregulating K+-Cl-cotransporter-2 in the spinal dorsal horn in rats[J]. J Pain Res,2018,11:993-1004.
[41]Ford A,Castonguay A,Cottet M,et al. Engagement of the GABA to KCC2 signaling pathway contributes to the analgesic effects of A3AR agonists in neuropathic pain[J]. J Neurosci,2015,35:6057-6067.
[42]He Y,Ji W,Huang H. Effect of the cation-chloride cotransporter inhibitor furosemide in a rat model of postoperative pain[J]. Pain Med,2011,12:1427-1434.
[43]Zhou HY,Chen SR,Byun HS,et al. N-Methyl-d-aspartate Receptor-and Calpain-mediated Proteolytic Cleavage of K+-Cl-Cotransporter-2 Impairs Spinal Chloride Homeostasis in Neuropathic Pain[J]. J Biol Chem,2012,287:33853-33864.
[44]Miletic G,Miletic V. Loose ligation of the sciatic nerve is associated with TrkB receptor-dependent decreases in KCC2 protein levels in the ipsilateral spinal dorsal horn[J]. Pain,2008,137:532-539.
[45]Rivera C,Li H,Thomas-Crusells J,et al. BDNF-induced Trk B activation down-regulates the K+-Cl-cotransporter KCC2 and impairs neuronal Cl-extrusion[J]. J Cell Biol,2002,159:747-752.
[46]代淑红,孙玉娥,荣辉,等. K252a通过下调脊髓背角钾氯共转运体-2的表达缓解大鼠术后持续性痛[J].国际麻醉学与复苏杂志,2016,37:426-429.
[47] Zhang Z,Wang X,Wang W,et al. Brain-derived neurotrophic factor-mediated downregulation of brainstem K+-Cl-otransporter and cell-type-specific GABA impairment for activation of descending pain facilitation[J]. Mol Pharmacol,2013,84:511-520.
[48]Shih HC,Kuan YH,Shyu BC. Targeting BDNF in the medial thalamus for the treatment of central poststroke pain in a rodent model[J]. Pain,2017,158:1302-1313.
[49]Gagnon M,Bergeron MJ,Lavertu G,et al. Chloride extrusion enhancers as novel therapeutics for neurological diseases[J]. Nat Med,2013,19:1524-1528.
[50]Ferrini F,Lorenzo LE,Godin AG,et al. Enhancing KCC2 function counteracts morphine-induced hyperalgesia[J]. Sci Rep,2017,7:3870.