Reduction of spike frequency adaptation and blockade of M‐current in rat CA1 pyramidal neurones by linopirdine (DuP 996), a neurotransmitter release enhancer

Abstract

1 Linopirdine (DuP 996) has been shown to enhance depolarization-induced release of several neurotransmitters in the CNS through a mechanism which may involve K+ channel blockade. The electrophysiological effects of linopirdine were therefore investigated directly, by use of conventional voltage recording and single electrode voltage-clamp.2 Linopirdine (10 gM) reduced spike frequency adaptation (SFA) in rat hippocampal CAl pyramidal neurones in vitro. The reduction of SFA comprised an increase in number of spikes and a reduction in inter-spike intervals after the first, but with no effect on time to first spike. Linopirdine also caused a voltage-dependent depolarization of resting membrane potential (RMP). 3 M-current (IM), a current known to underlie SFA and to set RMP, was blocked by linopirdine in a reversible, concentration-dependent manner (IC50 = 8.5 gM). This block was not reversed by atropine (10 gM).4 Linopirdine did not affect IQ, the slow after-hyperpolarization following a spike train, or spike duration. 5 Linopirdine may represent a novel class of K+ blocker with relative selectivity for the M-current. This block of IM is consistent with the suggestion from a previous study that linopirdine may affect a tetraethylammonium-sensitive channel, and it could be speculated that IM blockade may be involved with the enhancement of neurotransmitter release by linopirdine.

A Spontaneous Mutation InvolvingKcnq2(Kv7.2) Reduces M-Current Density and Spike Frequency Adaptation in Mouse CA1 Neurons

“…This result is consistent with the hypothesis that proper I K(M) function is an important component of normal SFA (Goh and Pennefather, 1987;Aiken et al, 1995). Another group, however, has shown that LPD does not affect SFA in cultured mouse and rat superior cervical ganglion neurons (Romero et al, 2004), although neurons of this population are not implicated in epilepsy.…”

“…Pharmacological block or enhancement of I K(M) depolarizes or hyperpolarizes resting membrane potential, respectively (Aiken et al, 1995;Otto et al, 2002;Peretz et al, 2005). Surprisingly, however, we found no significant change in resting membrane potential between B6 and Szt1 mice.…”

“…I K(M) activation repolarizes the cell and regulates neuronal excitability by controlling the generation and frequency of action potentials (Marrion, 1997). Accordingly, direct M-channel blockers and enhancers facilitate and inhibit action potential generation, respectively (Aiken et al, 1995;Otto et al, 2002). In relation to epilepsy, the M-channel blocker linopirdine is proconvulsant, whereas the enhancer retigabine is anticonvulsant (Flagmeyer et al, 1995;Rostock et al, 1996;Dost and Rundfeldt, 2000;Otto et al, 2004), and KCNQ2 and KCNQ3 gene mutations cause benign familial neonatal convulsions (BFNC), an idiopathic generalized human epilepsy (Biervert et al, 1998;Singh et al, 1998).…”

KV7/M Channels Mediate Osmotic Modulation of Intrinsic Neuronal Excitability

“…In CA1 pyramidal cells, the main K ϩ current counteracting I NaP and curtailing the spike ADP is I M (Yue and Yaari, 2004). Inhibiting this current with K V 7/M channel blockers, such as linopirdine or XE991 (Aiken et al, 1995;Wang et al, 1998), was shown to facilitate the spike ADP and induce bursting in striking resemblance to the effects of low osmolarity. Likewise, bursts induced by inhibiting I M were readily suppressed by inhibiting I NaP with riluzole and markedly prolonged by blocking Ca 2ϩ currents with 1 mM Ni 2ϩ .…”

AKAP150 signaling complex promotes suppression of the M-current by muscarinic agonists

“…Activation of G q/11 -coupled receptors suppresses the Mcurrent, creating a slow excitatory postsynaptic potential, enhancing excitability and reducing spike-frequency adaptation 1,2 . The M-type K + channel is a promising therapeutic target, as the channel blocker linopirdine acts as a cognition enhancer 3,4 , and the channel activator retigabine functions as an anticonvulsant 5,6 . M-type channels are heteromeric complexes of certain KCNQ-family potassium channel subunits (KCNQ2-5) [7][8][9][10] .…”