| 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 nicotonic 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 colchicine inhibited [3H]perhydrohistrionicotoxin ([3H]H12-HTX) binding to the receptor-gated ion channel with IC50 values of 2-32 μM and 6 mM, respectively. 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 μM carbamylcholine. The IC50 values for inhibition of [3H]H12-HTX binding by colchicine and three 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. β-Lumicolchicine, and analog of colchicine devoid of microtubule activity, also blocked ion channel binding. On the other hand, taxol, a microtubule-stabilizing agent which also selectively blocks cholinergically mediated secretion, did not affect receptor or ion channel binding. The present results indicate that interactions with the nicotinic receptor-ion channel complex may underlie the actions of certain microtubule-active agents on catecholamine secretion by adrenal chromaffin cells. |
| Keywords: |
drug efficacy; nonhuman; paclitaxel; animal cell; animal; vincristine; in vitro study; vinblastine; drug receptor binding; vindesine; cattle; vinca alkaloid; radioisotope; fish; alkaloids; microtubules; catecholamines; pharmacokinetics; in vitro; vinca alkaloids; colchicine; nervous system; drug interaction; taxol; nicotinic receptor; catecholamine release; ion channels; receptors, nicotinic; priority journal; chromaffin cell; chromaffin system; support, non-u.s. gov't; support, u.s. gov't, p.h.s.; receptors, muscarinic; secretory rate; carbachol; electric organ; lumicolchicine; microtubule inhibitory factor; noradrenalin h 3; perhydrohistrionicotoxin h 3; scopolamine h 3; amphibian venoms; torpedo
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