The 5‐HT4 receptor subtype inhibits K+ current in colliculi neurones via activation of a cyclic AMP‐dependent protein kinase

Abstract

1 The aim of the present study was to examine the effect of 5-hydroxytryptamine (5-HT) on K⁺ current in primary culture of mouse colliculi neurones and to identify the 5-HT receptor subtype that could be involved in this effect. 2 The voltage-activated K⁺ current of the neurones was partially blocked by 8-bromo adenosine 3′:5′-cyclic monophosphate (8-bromo-cyclic AMP). This effect was mimicked by 5-HT and the action of 5-HT could be antagonized by H7, a non specific protein kinase inhibitor, and by PKI, the specific cyclic AMP-dependent protein kinase blocker. 3 A similar cyclic AMP-dependent blockade of the K⁺ current was found with renzapride (BRL 24 924) and other 5-HT₄ receptor agonists such as cisapride, BIMU 8, zacopride and 5-methoxytryptamine (5-MeOT). ICS 205 930, the classical 5-HT₄ receptor blocker, could not be used in this study because it inhibited the studied K⁺ current by itself. However, the novel 5-HT₄ receptor antagonist, DAU 6285 blocked the effects of 5-HT and renzapride on the K⁺ current. 4 The current was insensitive to the 5-HT₁ and 5-HT₃ receptor agonists (8-hydroxy-2-(di-n-propylamino) tetralin, RU 24 969, carboxamidotryptamine, 2-CH₃-5-HT) as well as to 5-HT₁, 5-HT₂ and 5-HT₃ antagonists (methiothepin, ketanserin, ondansetron [GR 38 032]). Moreover, these antagonists did not affect the actions of the tested 5-HT₄ receptor agonists. 5 The present results show that part of the voltage-activated K⁺ current in mouse colliculi neurones is cyclic AMP-sensitive and the blockade of the current by 5-HT involves the 5-HT₄ receptor subtype. The putative implication of 5-HT₄ receptors in neuronal plasticity, via a blockade of K⁺ channels, is discussed.