Blockade of Ca2+ -activated K+ channels by galantamine can also contribute to the potentiation of catecholamine secretion from chromaffin cells.
Galantamine is a drug in clinical use for the treatment of Alzheimer's disease, but its mechanism(s) of action remains controversial. Here we addressed the question whether galantamine could potentiate neurotransmitter release by inhibiting small conductance Ca2+ -activated K+ channels (KCa2). Galantamine potentiated catecholamine secretory responses induced by 10 s pulses of acetylcholine and high [K+]o applied to fast-superfused bovine adrenal chromaffin cell populations. Catecholamine release was significantly enhanced by galantamine although we did not find concentration dependence in the range 0.1-1 microM. The KCa2 channel blocker apamin (0.3 microM) occluded the potentiating effects of galantamine on acetylcholine-evoked secretion. Like apamin, galantamine also modified the firing of action potentials, but to a lesser extent. In addition, 1 microM galantamine reduced by 41% the KCa2 current without modifying the voltage-dependent Ca2+ currents. These results constitute the first direct evidence that galantamine can potentiate neurotransmitter release by blocking KCa2 channels, in addition to its already demonstrated capacity to mildly block acetylcholinesterase or potentiate allosterically nicotinic receptors.
Alés
Eva
E
Instituto Teófilo Hernando. Departamento de Farmacología y Terapéutica, Facultad de Medicina, U.A.M., Universidad Autónoma de Madrid, C/, Arzobispo Morcillo 4, E-28029 Madrid - Spain.
Gullo
Francesca
F
Arias
Esperanza
E
Olivares
Román
R
García
Antonio G
AG
Wanke
Enzo
E
López
Manuela G
MG
D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000313:Adrenal Medulla / Q000166:cytology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D005702:Galantamine / Q000494:pharmacology*; D008297:Male; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000502:physiology
D002395:Catecholamines; D051640:Small-Conductance Calcium-Activated Potassium Channels; D005702:Galantamine; D001030:Apamin; D000109:Acetylcholine; D011188:Potassium