Abstract
The effect of nicotine on the major human neuronal nicotinic receptor (α4β2 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.
Footnotes
- Received April 18, 1997.
- Accepted August 16, 1997.
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Send reprint requests to: Dr. John R. Forsayeth, Neurex Corporation, 3760 Haven Avenue, Menlo Park, CA 94025-1012. E-mail:johnf{at}neurex.com
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This work was supported by a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft (H.E.) and by a grant from Pfizer, Inc. (J.F.).
- The American Society for Pharmacology and Experimental Therapeutics
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Functional Deactivation of the Major Neuronal Nicotinic Receptor Caused by Nicotine and a Protein Kinase C-Dependent Mechanism
