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Molecular Pharmacology

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Research ArticleArticle

Regulation of α4β2 Nicotinic Receptor Desensitization by Calcium and Protein Kinase C

Catherine P. Fenster, Matthew L. Beckman, Julie C. Parker, Elise B. Sheffield, Terri L. Whitworth, Michael W. Quick and Robin A. J. Lester
Molecular Pharmacology March 1999, 55 (3) 432-443;
Catherine P. Fenster
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Matthew L. Beckman
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Julie C. Parker
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Elise B. Sheffield
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Terri L. Whitworth
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Michael W. Quick
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Robin A. J. Lester
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Abstract

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 α4β2 nAChRs expressed in Xenopus laevis oocytes were investigated. Nicotine-induced (300 nM; 30 min) desensitization of α4β2 receptors in the presence of Ca2+ developed in a biphasic manner with fast and slow exponential time constants of τf = 1.4 min (65% relative amplitude) and τs = 17 min, respectively. Recovery from desensitization was reasonably well described by a single exponential with τrec = 43 min. Recovery was largely eliminated after replacement of external Ca2+ with Ba2+ and slowed by calphostin C (τrec = 48 min), an inhibitor of PKC. Conversely, the rate of recovery was enhanced by phorbol-12-myristate-13-acetate (τrec = 14 min), a PKC activator, or by cyclosporin A (with τrec = 8 min), a phosphatase inhibitor. α4β2 receptors containing a mutant α4 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, α4β2 nAChRs accumulate in a “deep” desensitized state, from which recovery is very slow. We suggest that PKC-dependent phosphorylation of α4 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 α4β2 receptors observed after chronic nicotine treatment.

Footnotes

  • Send reprint requests to: Dr. Robin A.J. Lester, Department of Neurobiology, Civitan International Research Center 560, 1719 Sixth Avenue South, Birmingham AL 35294-0021. E-mail:rlester{at}nrc.uab.edu

  • This research was supported by United States Public Health Service Grants DA11940 and NS31669 (R.A.J.L.) and the W. M. Keck Foundation 931360. M.L.B. is sponsored in part by the Medical Scientist Training Program. J.C.P. is sponsored by the Neuroscience Training Program.

  • Abbreviations:
    CNS
    central nervous system
    nAChR
    nicotinic acetylcholine receptor
    PKC
    protein kinase C
    PKA
    protein kinase A
    PMA
    phorbol-12-myristate-13-acetate
    • Received July 17, 1998.
    • Accepted November 25, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (3)
Molecular Pharmacology
Vol. 55, Issue 3
1 Mar 1999
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Research ArticleArticle

Regulation of α4β2 Nicotinic Receptor Desensitization by Calcium and Protein Kinase C

Catherine P. Fenster, Matthew L. Beckman, Julie C. Parker, Elise B. Sheffield, Terri L. Whitworth, Michael W. Quick and Robin A. J. Lester
Molecular Pharmacology March 1, 1999, 55 (3) 432-443;

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Research ArticleArticle

Regulation of α4β2 Nicotinic Receptor Desensitization by Calcium and Protein Kinase C

Catherine P. Fenster, Matthew L. Beckman, Julie C. Parker, Elise B. Sheffield, Terri L. Whitworth, Michael W. Quick and Robin A. J. Lester
Molecular Pharmacology March 1, 1999, 55 (3) 432-443;
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