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Vol. 280, Issue 3, 1192-1200, 1997
-Aminobutyric
Acid Receptors to Ethanol Involves a Cyclic AMP/Protein Kinase A
Second-Messenger Mechanism1
Department of Pharmacology, University of Colorado Health Sciences
Center, Denver, Colorado
Previous studies have found that ethanol (EtOH) will consistently
potentiate 
-aminobutyric acid (GABA) receptor function in the
cerebellum during beta adrenergic receptor activation. One consequence of beta adrenergic receptor stimulation
is to increase cAMP levels, which, in turn, activate protein kinase A
(PKA)-mediated phosphorylation of intracellular protein sites. In the
present study, we investigated three cAMP analogues, two activators and
one inhibitor of PKA to determine whether this cAMP-mediated
second-messenger system may be one mechanism involved in the previously
observed beta adrenergic interaction of EtOH with the
GABAA receptor. Furthermore, because the phosphorylation state of the GABAA receptor may be an important determinant
of function, we investigated the effect of the block of phosphatase activity on EtOH/GABA receptor interactions. We found that similar to
the beta adrenergic agonist isoproterenol, local
applications of the membrane-permeable cAMP analogues 8-bromo-cAMP and
Sp-cAMP could modulate responses to iontophoretically applied GABA and that these modulated GABA responses were sensitized to the potentiative effects of EtOH. EtOH did not facilitate unmodulated GABA effects or
GABA responses that were maximally modulated by 8-bromo-cAMP, suggesting that the cAMP mechanism mediates the observed EtOH interaction with GABA mechanisms. Furthermore, the PKA inhibitor Rp-cAMP reversed the EtOH-induced potentiation of the
isoproterenol-modulated GABA responses. Finally, microcystin-LR and
okadaic acid, which are type I and IIa phosphatase inhibitors, could
also modulate and sensitize GABA responses to EtOH. These data suggest
that beta adrenergic sensitization of GABAA
receptors to EtOH involves the intracellular cAMP/PKA second-messenger
cascade.
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