ETHANOL POTENTIATION OF GABA(A) RECEPTORS REQUIRES PHOSPHORYLATION OF THE ALTERNATIVELY SPLICED VARIANT OF THE GAMMA-2 SUBUNIT

The mammalian GABA(A) receptor is a multisubunit protein containing a variety of binding sites for psychotropic agents. One of the most widely used of these drugs, ethanol, enhances the function of GABA(A) receptors in certain circumstances but not others. Previous studies have demonstrated that alternative splicing of the gamma2L GABA subunit results in an ethanol sensitive and an ethanol-insensitive form, when combined with alpha and beta subunits. We have used in vitro mutagenesis and expression in Xenopus oocytes to show that the consensus site for phosphorylation by protein kinase C contained in the gamma2L insert is critical for modulation by ethanol but not benzodiazepines, and manipulation of the phosphorylating enzymes in oocytes containing alpha1beta1gamma2L can prevent ethanol enhancement. It is likely that phosphorylation or dephosphorylation of a specific site on the GABA(A) receptor protein can act as a control mechanism for neuronal responses to alcohol exposure.