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M channels containing KCNQ2 subunits modulate norepinephrine, aspartate, and GABA release from hippocampal nerve terminals.

Maria Martire, Pasqualina Castaldo, Monia D'Amico, Paolo Preziosi, Lucio Annunziato, Maurizio Taglialatela

J. Neurosci., 2004 Jan 21 , 24, 592-7

KCNQ subunits encode for the M current (I(KM)), a neuron-specific voltage-dependent K+ current with a well established role in the control of neuronal excitability. In this study, by means of a combined biochemical, pharmacological, and electrophysiological approach, the role of presynaptic I(KM) in the release of previously taken up tritiated norepineprine (NE), GABA, and d-aspartate (d-ASP) from hippocampal nerve terminals (synaptosomes) has been evaluated. Retigabine (RT) (0.01-30 microm), a specific activator of I(KM), inhibited [3H]NE, [3H]d-ASP, and [3H]GABA release evoked by 9 mm extracellular K+ ([K+]e). RT-induced inhibition of [3H]NE release was prevented by synaptosomal entrapment of polyclonal antibodies directed against KCNQ2 subunits, an effect that was abolished by antibody preabsorption with the KCNQ2 immunizing peptide; antibodies against KCNQ3 subunits were ineffective. Flupirtine (FP), a structural analog of RT, also inhibited 9 mm [K+]e-induced [3H]NE release, although its maximal inhibition was lower than that of RT. Electrophysiological studies in KCNQ2-transfected Chinese hamster ovary cells revealed that RT and FP (10 microm) caused a -19 and -9 mV hyperpolarizing shift, respectively, in the voltage dependence of activation of KCNQ2 K+ channels. In the same cells, the cognition enhancer 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE-991) (10 microm) blocked KCNQ2 channels and prevented their activation by RT (1-10 microm). Finally, both XE-991 (10-100 microm) and tetraethylammonium ions (100 microm) abolished the inhibitory effect of RT (1 microm) on [3H]NE release. These findings provide novel evidence for a major regulatory role of KCNQ2 K+ channel subunits in neurotransmitter release from rat hippocampal nerve endings.