Involvement of KCNQ2 subunits in [³H]dopamine release triggered by depolarization and pre‐synaptic muscarinic receptor activation from rat striatal synaptosomes

Abstract

H]DA release enhancement was competitively inhibited by pirenzepine (1-10 nmol/L) and abolished by the M 3 -preferring antagonist 4-diphenylacetoxy N-methylpiperidine methiodide (1 lmol/L), but was unaffected by the M 1 -selective antagonist MT-7 (10-100 nmol/L) or by Pertussis toxin (1.5-3 lg/mL), which uncouples M 2 -and M 4 -mediated responses. Finally, OXO-induced potentiation of depolarization-induced [ 3 H]DA release was not additive to that produced by XE-991 (10 lmol/L), was unaffected by retigabine (10 lmol/L), and was abolished by synaptosomal entrapment of anti-KCNQ2 antibodies. Collectively, these findings indicate that, in rat striatal nerve endings, I KM channels containing KCNQ2 subunits regulate depolarization-induced DA release and that I KM suppression is involved in the reinforcement of depolarization-induced DA release triggered by the activation of pre-synaptic muscarinic heteroreceptors.

Protective Role of Kv7 Channels in Oxygen and Glucose Deprivation-Induced Damage in Rat Caudate Brain Slices

“…In particular, linopirdine prevented the effect on T on exerted by retigabine, although it did not modify this parameter when incubated alone, thus arguing in favor of a specific involvement of the M current. By contrast, the linopirdine-analog XE-991 (10 μmol/L) did not modulate OGDevoked dopamine efflux, although it was previously showed that it increased depolarization-induced dopamine efflux from isolated striatal synaptosomes 14 and from striatal brain slices. 21 Differences in the experimental models (isolated terminals/chopped slices vs brain slices) as well as in the experimental procedures (KCl-vs OGD-evoked release, preincubation with dopamine reuptake inhibitors) might explain this discrepancy.…”

“…19 Dopamine and related compound such as L-3,4-dihydroxyphenylalanine and 6-OH-DOPA are considered as potent excitotoxic agents, possibly contributing to neurodegeneration in Parkinson's and Huntington's disease. 20 Given the known effect of the antiepileptic drug retigabine in reducing dopamine release, 14,21 we have investigated the possibility that the pharmacological activation of K v 7-mediated currents could exert a neuroprotective effect in an in vitro model of ischemia. In particular, we focused on the striatum, a region frequently damaged in ischemic stroke in humans and rodent models of stroke, such as middle cerebral artery occlusion.…”

“…13 In particular, the K v 7 activator retigabine, a recently marketed antiepileptic drug used as an adjunctive treatment in patients with refractory epilepsy, was able to decrease dopamine release from isolated striatal nerve terminals exposed to high extracellular K + concentrations. 14 In addition, while some studies have shown that K v 7 activators reduced neuronal damage in hippocampal brain slices, 15,16 others found that M-current activation increased death in hippocampal cultured neurons. 17 The aim of this study was to investigate the potential neuroprotective role of K v 7 channels in an in vitro model of ischemia, by evaluating the pharmacological modulation of K v 7 channels on dopamine efflux and on neurotoxicity in rat caudate, a region often damaged in ischemic stroke.…”

Regulation of Neuronal M-Channel Gating in an Isoform-Specific Manner: Functional Interplay between Calmodulin and Syntaxin 1A

“…Syx has been shown to colocalize with and to bind Q2-containing channels at hippocampal presynaptic boutons and in synaptosomal membranes (Regev et al, 2009). CaM may regulate neurotransmitter release through modulation of presynaptic M-current, either by control of axonal action potential firing or via direct effect on presynaptic M-channels (Martire et al, 2004(Martire et al, , 2007Peretz et al, 2007;Hernandez et al, 2008). One such direct mechanism could be mediated by Ca 2ϩ activation of CaM bound to M-channels through presynaptic bradykinin receptor activation (Trendelenburg et al, 2000).…”

Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels

“…Both Kv7/KCNQ channels and GHS-R are expressed in the SNc, hippocampus, dorsal root ganglion (DRG), hypothalamus and cortex 11,15,[17][18][19][20][21][22][23] . KCNQ channels are also negatively modulated by G-protein-coupled receptors via Gq and/ or G 11 activated phospholipase C (PLC)-mediated signal pathway [24][25][26] .…”