The 5-HT4 receptor subtype inhibits K+ current in colliculi neurones via activation of a cyclic AMP-dependent protein kinase.
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.
Fagni
L
L
Centre de Pharmacologie et d'Endocrinologie, Montpellier, France.
Dumuis
A
A
Sebben
M
M
Bockaert
J
J
D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D013477:Superior Colliculi / Q000187:drug effects / Q000378:metabolism*
D011985:Receptors, Serotonin; D012701:Serotonin; D000242:Cyclic AMP; D011494:Protein Kinases; D011188:Potassium