Neural KCNQ (Kv7) channels

British Journal of Pharmacology - Tập 156 Số 8 - Trang 1185-1195 - 2009
David A. Brown1, Gayle M. Passmore1
1Department of Pharmacology, University College London, London, UK

Tóm tắt

KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage‐gated M‐channel, which widely regulates neuronal excitability, although other subunits may contribute to M‐like currents in some locations. M‐channels are closed by receptors coupled to Gq such as M1 and M3 muscarinic receptors; this increases neuronal excitability and underlies some forms of cholinergic excitation. Muscarinic closure results from activation of phospholipase C and consequent hydrolysis and depletion of membrane phosphatidylinositol‐4,5‐bisphosphate, which is required for channel opening. Some effects of M‐channel closure, determined from transmitter action, selective blocking drugs (linopirdine and XE991) and KCNQ2 gene disruption or manipulation, are as follows: (i) in sympathetic neurons: facilitation of repetitive discharges and conversion from phasic to tonic firing; (ii) in sensory nociceptive systems: facilitation of A‐delta peripheral sensory fibre responses to noxious heat; and (iii) in hippocampal pyramidal neurons: facilitation of repetitive discharges, enhanced after‐depolarization and burst‐firing, and induction of spontaneous firing through a reduction of action potential threshold at the axon initial segment. Several drugs including flupirtine and retigabine enhance neural Kv7/M‐channel activity, principally through a hyperpolarizing shift in their voltage gating. In consequence they reduce neural excitability and can inhibit nociceptive stimulation and transmission. Flupirtine is in use as a central analgesic; retigabine is under clinical trial as a broad‐spectrum anticonvulsant and is an effective analgesic in animal models of chronic inflammatory and neuropathic pain.

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Tài liệu tham khảo

Adams PR, 1986, Slow synaptic transmission in frog sympathetic ganglia, J Exp Biol, 124, 259, 10.1242/jeb.124.1.259

10.1111/j.1476-5381.1995.tb15019.x

10.1016/S1054-3589(08)60281-1

10.1016/j.neuropharm.2006.07.001

10.1016/S0014-2999(02)02924-2

10.1016/0166-2236(83)90144-3

Brown DA, 1986, Fast and Slow Chemical Signalling in the Nervous System, 130

10.1007/978-1-4615-7302-9_2

10.1038/283673a0

10.1113/jphysiol.1985.sp015554

10.1111/j.1476-5381.1987.tb10279.x

10.1113/jphysiol.2007.148171

10.1073/pnas.0603376103

10.1016/j.yebeh.2007.09.023

10.1523/JNEUROSCI.4512-03.2004

10.1007/s00210-004-0881-1

10.1113/jphysiol.1981.sp013865

10.2165/00003495-199345040-00007

10.1517/14728222.12.5.565

10.1523/JNEUROSCI.23-12-05012.2003

10.1016/0006-8993(82)90954-4

10.1016/j.ejphar.2007.05.029

10.1113/jphysiol.2007.149450

10.1085/jgp.200810007

10.1007/s00424-007-0259-6

10.1038/35036198

10.1111/j.1476-5381.1986.tb10175.x

10.1124/jpet.105.083923

10.1016/j.neuropharm.2008.04.006

10.1007/s00424-007-0276-5

10.1113/jphysiol.1984.sp015378

10.1124/mol.58.2.253

10.1113/jphysiol.2008.150656

10.1146/annurev.physiol.59.1.483

10.1016/j.coph.2007.10.003

10.1016/j.neuropharm.2007.07.002

10.1124/mol.61.4.921

10.1523/JNEUROSCI.4314-05.2006

Passmore GM, 2007, Effects of M‐channel modulators on peripheral excitability in rat hairy skin, Abstr Soc Neurosci, 681, 8

Passmore GM, 2003, KCNQ/M currents in sensory neurons: significance for pain therapy, J Neurosci, 23, 7236, 10.1523/JNEUROSCI.23-18-07227.2003

Passmore GM, 2006, The KCNQ2 (Kv7.2) gene is required for functional M‐channels in embryonic mouse superior cervical ganglion (SCG) neurons, Proc Physiol Soc, 3, C106

10.1124/mol.104.007112

10.1371/journal.pone.0001332

10.1038/nn1375

10.1212/01.wnl.0000259034.45049.00

10.1113/jphysiol.2008.153791

10.1242/jcs.03396

10.1016/0304-3940(86)90180-1

10.1016/j.neuropharm.2006.05.015

10.1016/S0163-7258(01)00116-4

10.1523/JNEUROSCI.2138-06.2006

10.1017/S031716710002148X

10.1124/jpet.108.137794

10.1016/0920-1211(95)00101-8

10.1523/JNEUROSCI.0128-05.2005

10.1016/S0028-3908(01)00029-6

10.1113/jphysiol.2006.106815

10.1111/j.1469-7793.1998.071bz.x

10.1098/rspb.1992.0139

10.1111/j.1469-7793.2000.t01-2-00349.x

10.1113/jphysiol.2002.028571

10.1073/pnas.0802805105

10.1016/j.toxicon.2003.12.009

10.1016/S0896-6273(02)00790-0

10.1085/jgp.200409029

10.1126/science.1131163

10.1113/jphysiol.2003.039842

10.1523/JNEUROSCI.21-15-05535.2001

10.1113/jphysiol.1995.sp020732

10.1126/science.282.5395.1890

Wang HS, 2000, Molecular basis for differential sensitivity of KCNQ and I(Ks) channels to the cognitive enhancer XE991, Mol Pharmacol, 57, 1218

10.1124/mol.58.3.591

10.1124/mol.107.043216

10.1074/jbc.273.9.5037

10.1523/JNEUROSCI.3231-04.2005

10.1113/jphysiol.2007.145284

10.1124/mol.104.010793

10.1038/nchembio874

10.1073/pnas.0712256105

Yamada W, 1998, Methods in Neuronal Modelling: from Synapse to Networks, 137

10.1523/JNEUROSCI.0765-04.2004

10.1113/jphysiol.2006.114074

10.1016/S0896-6273(03)00125-9

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British Journal of Pharmacology

Tập 156 Số 8

1185-1195

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