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Vol. 52, Issue 6, 1105-1112, 1997

Functional Deactivation of the Major Neuronal Nicotinic Receptor Caused by Nicotine and a Protein Kinase C-Dependent Mechanism

Helge Eilers, Eric Schaeffer, Philip E. Bickler, and John R. Forsayeth

Department of Anesthesia, University of California San Francisco, San Francisco, California 94143-0542 (H.E., P.E.B.), Pfizer, Inc., Central Research Division, Groton, Connecticut 06340 (E.S.), and Neurex Corporation, Menlo Park, California 94025 (J.R.F.)

The effect of nicotine on the major human neuronal nicotinic receptor (alpha 4beta 2 subtype) was studied in permanently transfected HEK 293 cells. Prolonged exposure to low concentrations of nicotine (1 µM) increased epibatidine binding but functionally deactivated the nicotinic receptor, abolishing Ca2+ influx in response to an acute nicotine challenge. Deactivation could also be caused by down-regulating protein kinase C (PKC) activity with 0.5 µM phorbol-12,13-dibutyrate or briefly incubating cells with the PKC inhibitor NPC-15437. Recovery from receptor deactivation caused by either nicotine treatment or PKC inhibition occurred slowly (4-6 hr). Reversal of nicotine-induced deactivation was accelerated by the addition of inhibitors of protein phosphatases 2A and 2B. These data suggest a hypothetical mechanism of nicotine-induced deactivation that involves dephosphorylation of nicotinic receptors at PKC phosphorylation sites.

Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics


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