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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Protein Kinase A Regulates Inhibition of N- and P/Q-type Calcium Channels by Ethanol in PC12 Cells

Michele Solem, Thomas McMahon and Robert O. Messing
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1487-1495;
Michele Solem
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Thomas McMahon
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Robert O. Messing
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Abstract

Ethanol inhibits L-type Ca++ channels, but little is known about its effect on other voltage-gated Ca++ channels. To examine non-L-type channels we used nerve growth factor-differentiated PC12 cells treated with the L channel blocker nifedipine. Using selective Ca++ channel antagonists, we found that N-type and P/Q -type channels mediate most of the remaining depolarization-evoked Ca++ rise. Ethanol (10–150 mM) inhibited depolarization-induced rises in intracellular Ca++ with maximal inhibition of 46% achieved using 50 mM ethanol. Inhibition was time dependent, requiring at least 8 min to develop fully. Ethanol did not alter Ca++ mobilization, sequestration, extrusion or capacitative entry. Sp-adenosine cyclic 3′,5′-phosphorothioate, a specific activator of protein kinase A (PKA), blocked inhibition by ethanol, whereas the protein kinase C activator phorbol 12-myristate, 13-acetate did not. Okadaic acid, an inhibitor of protein phosphatases type-1 and type-2A, also blocked inhibition by ethanol with an IC50 of 3 nM. This was prevented by inhibiting PKA, indicating that the action of okadaic acid was due to increased PKA-mediated phosphorylation. These results indicate that ethanol can inhibit N-type and P/Q-type channels and this is antagonized by activating PKA. The findings suggest the sensitivity of these channels to ethanol is regulated by a phosphoprotein that is a substrate for PKA and protein phosphatase type-2A.

Footnotes

  • Send reprint requests to: Dr. Robert O. Messing, Building 1, Room 101, 1001 Potrero Avenue, San Francisco, CA 94110.

  • ↵1 This work was supported by grants from the National Institute on Alcohol Abuse and Alcoholism and the Alcoholic Beverage Medical Research Foundation (R.O.M.).

  • Abbreviations:
    PKA
    protein kinase A
    PKC
    protein kinase C
    GABA
    γ-aminobutyric acid
    AMPA
    α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
    Sp-cAMPS
    Sp-adenosine cyclic 3′, 5′-phosphorothioate
    Rp-cAMPS
    Rp-adenosine cyclic 3′, 5′-phosphorothioate
    DMEM
    Dulbecco’s modified Eagle’s medium
    cAMP
    cyclic adenosine monophosphate
    EGTA
    ethylene glycol bis(β-aminoethyl ester)-N, N′-tetraacetic acid
    HEPES
    N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid]
    [Ca2+]i
    intracellular calcium concentration
    PP-1 protein phosphatase type-1
    PP-2A, protein phosphatase type-2A
    PP-2B
    protein phosphatase type-2B
    • Received March 4, 1997.
    • Accepted May 23, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Protein Kinase A Regulates Inhibition of N- and P/Q-type Calcium Channels by Ethanol in PC12 Cells

Michele Solem, Thomas McMahon and Robert O. Messing
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1487-1495;

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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Protein Kinase A Regulates Inhibition of N- and P/Q-type Calcium Channels by Ethanol in PC12 Cells

Michele Solem, Thomas McMahon and Robert O. Messing
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1487-1495;
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