Interactions of microtubule-active agents with nicotinic acetylcholine receptors. Relationship to their inhibition of catecholamine secretion by adrenal chromaffin cells.
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 colchicine inhibited [3H]perhydrohistrionicotoxin ([3H]H12-HTX) binding to the receptor-gated ion channel with IC50 values of 2-32 microM 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 microM 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. beta-Lumicolchicine, an 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.
D B
DB
McKay
R S
RS
Aronstam
A S
AS
Schneider
D000470:Alkaloids / Q000494:pharmacology; D000664:Amphibian Venoms / Q000494:pharmacology; D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D002838:Chromaffin System / Q000378:metabolism*; D003078:Colchicine / Q000494:pharmacology; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects*; D017239:Paclitaxel; D011976:Receptors, Muscarinic / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects*; D012636:Secretory Rate / Q000187:drug effects; D014101:Torpedo; D014748:Vinca Alkaloids / Q000494:pharmacology
D000470:Alkaloids; D000664:Amphibian Venoms; D002395:Catecholamines; D007473:Ion Channels; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D014748:Vinca Alkaloids; D017239:Paclitaxel; D003078:Colchicine; C007948:histrionicotoxin