Effects of antimitotic agents on secretion and detergent extractibility of adrenal nicotinic acetylcholine receptors.
1. Evidence exists that associations of adrenal nicotinic acetylcholine receptors (nAChRs) with the cytoskeleton play an important role in signal transduction pathways by maintaining these receptors in a functional state. These studies were designed to explore this possibility and elucidate the mechanism by which antimitotic agents inhibit activation of adrenal nAChRs. 2. Functional studies demonstrated that vincristine, tubulozole, podophyllotoxin, and demecolcine inhibited nAChR-stimulated catecholamine release noncompetitively and in a concentration-dependent manner, with IC50 values of 3 (1-10), 5 (2-10), 8 (4-15), and 19 (9-39) microM, respectively. 3. Detergent extraction experiments indicated that approximately 36% of adrenal nAChRs were associated with the detergent-insoluble cytoskeletal fraction. When chromaffin cells were first treated with antimitotic agents and then detergent solubilized, a significant reduction occurred in the population of adrenal nAChRs associated with the detergent-insoluble cytoskeleton. 4. These studies support an association of adrenal nAChRs with microtubules and suggest that the mechanism by which the antimitotic drugs interfere with the signal transduction pathway is by inducing dissociation of nAChRs from the microtubular network.
Lopez
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Division of Pharmacology, Ohio State University, College of Pharmacy, Columbus 43210, USA.
McKay
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DB
D000311:Adrenal Glands / Q000166:cytology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002395:Catecholamines / Q000378:metabolism; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000737:chemistry* / Q000166:cytology / Q000187:drug effects*; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D003703:Demecolcine / Q000494:pharmacology; D003902:Detergents / Q000494:pharmacology; D004148:Dioxolanes / Q000494:pharmacology; D004158:Diphenylacetic Acids / Q000494:pharmacology; D008464:Mecamylamine / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology; D011034:Podophyllotoxin / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000302:isolation & purification* / Q000378:metabolism*; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002395:Catecholamines; D003902:Detergents; D004148:Dioxolanes; D004158:Diphenylacetic Acids; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010276:Parasympatholytics; D011978:Receptors, Nicotinic; D014750:Vincristine; C040422:tubulazole; D008464:Mecamylamine; D009538:Nicotine; D011034:Podophyllotoxin; C084829:adiphenine; D003703:Demecolcine