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The Journal of Neuroscience, June 15, 1999, 19(12):4804-4814
Upregulation of Surface  4 2 Nicotinic Receptors Is Initiated
by Receptor Desensitization after Chronic Exposure to Nicotine
Catherine P.
Fenster,
Terri L.
Whitworth,
Elise B.
Sheffield,
Michael W.
Quick, and
Robin A. J.
Lester
Department of Neurobiology, University of Alabama at Birmingham,
Birmingham, Alabama 35294
It is hypothesized that desensitization of neuronal nicotinic
acetylcholine receptors (nAChRs) induced by chronic exposure to
nicotine initiates upregulation of nAChR number. To test this hypothesis directly, oocytes expressing  4 2 receptors were
chronically incubated (24-48 hr) in nicotine, and the resulting
changes in specific [3H]nicotine binding to
surface receptors on intact oocytes were compared with functional
receptor desensitization. Four lines of evidence strongly support the
hypothesis. (1) The half-maximal nicotine concentration necessary to
produce desensitization (9.7 nM) was the same as that
needed to induce upregulation (9.9 nM). (2) The
concentration of [3H]nicotine for half-maximal
binding to surface nAChRs on intact oocytes was also similar (11.1 nM), as predicted from cyclical desensitization models. (3)
Functional desensitization of 34 receptors required 10-fold
higher nicotine concentrations, and this was mirrored by a 10-fold
shift in concentrations necessary for upregulation. (4) Mutant 42
receptors that do not recover fully from desensitization, but not
wild-type channels, were upregulated after acute (1 hr) applications of
nicotine. Interestingly, the nicotine concentration required for
half-maximal binding of 42 receptors in total cell membrane
homogenates was 20-fold lower than that measured for surface nAChRs in
intact oocytes. These data suggest that cell homogenate binding assays
may not accurately reflect the in vivo desensitization
affinity of surface nAChRs and may account for some of the previously
reported differences in the efficacy of nicotine for inducing nAChR
desensitization and upregulation.
Key words:
nicotine addiction; Xenopus oocytes; regulation; ion channel; radiolabeled binding; nicotinic receptor
subtypes; CNS
Copyright © 1999 Society for Neuroscience 0270-6474/99/19124804-11$05.00/0
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