INTERACTIONS OF MICROTUBULE-ACTIVE AGENTS WITH NICOTINIC ACETYLCHOLINE-RECEPTORS - RELATIONSHIP TO THEIR INHIBITION OF CATECHOLAMINE SECRETION BY ADRENAL CHROMAFFIN CELLS

  • 1 January 1985
    • journal article
    • research article
    • Vol. 28  (1) , 10-16
Abstract
Several microtubule-active drugs block cholinergically mediated catecholamine secretion from adrenal chromaffin cells without affecting secretion induced by other secretagogues. Interactions of these agents with nicotinic acetylcholine receptor-ion channel complexes from Torpedo californica electric organs were studied using radiolabeled probes for receptor and associated ion channel-binding sites. Colchicine, taxol and the Vinca alkaloids had minimal affinity for cholinergic receptor-binding sites (nicotinic or muscarinic). The Vinca alkaloids (vinblastine, vincristine, vindesine) and cholchicine inhibited [3H]perhydrohistrionicotoxin ([3H]H12-HTX) binding to the receptor-gated ion channel with IC50 [concentration giving 50% inhibition] values of 2-32 .mu.M and 6 mM, respctively. The ability of the microtubule-active drugs to inhibit [3H]H12-HTX binding was increased by up to 5-fold in the presence of 1 .mu.M carbamylcholine. The IC50 values for inhibition of [3H]H12-HTX binding by colchicine and 3 Vinca alkaloids were closely correlated with their abilities to inhibit acetylcholine-induced catecholamine secretion from cultured bovine adrenal chromaffin cells. As a consequence of its interaction (direct or indirect) with the ion channel, at least one Vinca alkaloid (vinblastine) stabilized a high agonist affinity conformation of the nicotinic receptor complex. .beta.-Lumicolchicine, an analog of colchicine devoid of microtuble activity, also blocked ion channel binding. Taxol, a microtubule-stabilizing agent which also selectively blocks cholinergically mediated secretion, did not affect receptor or ion channel binding. Interactions with the nicotinic receptor-ion channel complex may underlie the actions of certain microtubule-active agents on catecholamine secretion by adrenal chromaffin cells.