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Vol. 55, Issue 3, 432-443, March 1999
4
2 Nicotinic Receptor Desensitization by
Calcium and Protein Kinase C
Department of Neurobiology, University of Alabama at Birmingham,
Birmingham, Alabama
Neuronal nicotinic acetylcholine receptor (nAChR) desensitization is
hypothesized to be a trigger for long-term changes in receptor number
and function observed after chronic administration of nicotine at
levels similar to those found in persons who use tobacco.
Factors that regulate desensitization could potentially influence the
outcome of long-lasting exposure to nicotine. The roles of
Ca2+ and protein kinase C (PKC) on desensitization of
4
2 nAChRs expressed in Xenopus laevis oocytes were
investigated. Nicotine-induced (300 nM; 30 min) desensitization of
42 receptors in the presence of Ca2+ developed
in a biphasic manner with fast and slow exponential time constants of
f = 1.4 min (65% relative amplitude) and
s = 17 min, respectively. Recovery from desensitization
was reasonably well described by a single exponential with
rec = 43 min. Recovery was largely eliminated after
replacement of external Ca2+ with Ba2+ and
slowed by calphostin C (rec = 48 min), an inhibitor of
PKC. Conversely, the rate of recovery was enhanced by
phorbol-12-myristate-13-acetate (rec = 14 min), a PKC
activator, or by cyclosporin A (with rec = 8 min), a
phosphatase inhibitor. 42 receptors containing a mutant 4
subunit that lacks a consensus PKC phosphorylation site exhibited
little recovery from desensitization. Based on a two-desensitized-state cyclical model, it is proposed that after prolonged nicotine treatment, 42 nAChRs accumulate in a "deep" desensitized state, from
which recovery is very slow. We suggest that PKC-dependent
phosphorylation of 4 subunits changes the rates governing the
transitions from "deep" to "shallow" desensitized conformations
and effectively increases the overall rate of recovery from
desensitization. Long-lasting dephosphorylation may underlie the
"permanent" inactivation of 42 receptors observed after
chronic nicotine treatment.
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