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Research ArticleArticle

Maintenance of Recombinant Type A γ-Aminobutyric Acid Receptor Function: Role of Protein Tyrosine Phosphorylation and Calcineurin

Ren-Qi Huang and Glenn H. Dillon
Journal of Pharmacology and Experimental Therapeutics July 1998, 286 (1) 243-255;
Ren-Qi Huang
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Glenn H. Dillon
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Abstract

In the present study, rundown of γ-aminobutyric acid (GABA)-activated Cl− channels was studied in recombinant GABAAreceptors stably expressed in human embryonic kidney cells (HEK 293), with conventional whole-cell and amphotericin B-perforated patch recording. When [ATP]i was lowered to 1 mM and resting [Ca++]i was buffered to a relatively high level, the response of α3 β2 γ2 GABAA receptors to relatively low [GABA] (up to 50 μM) did not show rundown in the whole-cell configuration. However, high [GABA] (greater than 200 μM) induced significant rundown, which was observed by decreases in both the maximum GABA-induced current and GABA EC50. Rundown was prevented completely with a solution containing 4 mM Mg++-ATP and low resting [Ca++]i, or during perforated patch recording. The magnitude of rundown was comparable in α1 β2 γ2 and β2 γ2 receptors. Neither stimulation nor inhibition of protein kinase A or protein kinase C had a significant effect on rundown. However, sodium metavanadate, an inhibitor of protein tyrosine phosphatase, significantly reduced rundown. In addition, inhibition of protein tyrosine kinase activity by either genistein or lavendustin A induced rundown of the GABA response. Inhibition of the Ca++/calmodulin-dependent phosphatase calcineurin with fenvalerate also prevented rundown of the response to GABA. Our results demonstrate that rundown of GABAAreceptor function is concentration-dependent, due to depletion of ATP and/or unbuffered [Ca++]i, and does not depend on the presence or subtype of the alpha subunit. We propose that protein phosphorylation at a tyrosine kinase-dependent site, and a distinct unidentified site, which is dephosphorylated by calcineurin, maintains the function of GABAA receptors.

Footnotes

  • Send reprint requests to: Glenn H. Dillon, Ph.D., Dept. of Pharmacology, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Blvd., Fort Worth, TX 76107.

  • ↵1 Supported by National Institutes of Health grant ES07904, American Heart Association, Texas Affiliate grant 95G-158 and Texas Advanced Research Program grant 009768–027.

  • Abbreviations:
    GABA
    γ-aminobutyric acid
    GABAA
    type A GABA receptor
    D-cAMP
    adenosine 3′,5′-cyclic monophosphate N6O6 dioctanoyl sodium salt
    EGTA
    ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
    H-7
    (5-iosquinolinylsulfonyl)-2 methyl-piperazine dihydrochloride
    HEK
    human embryonic kidney
    HEPES
    N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid
    NaVO3
    sodium metavanadate
    NMDA
    N-methyl-d-aspartate
    PKC
    protein kinase C
    PKA
    protein kinase A
    PMA
    phorbol 12-myristate 13-acetate
    PTK
    protein tyrosine kinase
    PTP
    protein tyrosine phosphatase
    • Received January 15, 1998.
    • Accepted March 6, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 286, Issue 1
1 Jul 1998
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Research ArticleArticle

Maintenance of Recombinant Type A γ-Aminobutyric Acid Receptor Function: Role of Protein Tyrosine Phosphorylation and Calcineurin

Ren-Qi Huang and Glenn H. Dillon
Journal of Pharmacology and Experimental Therapeutics July 1, 1998, 286 (1) 243-255;

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Research ArticleArticle

Maintenance of Recombinant Type A γ-Aminobutyric Acid Receptor Function: Role of Protein Tyrosine Phosphorylation and Calcineurin

Ren-Qi Huang and Glenn H. Dillon
Journal of Pharmacology and Experimental Therapeutics July 1, 1998, 286 (1) 243-255;
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