Ethanol potentiation of GABAA receptors requires phosphorylation of the alternatively spliced variant of the γ2 subunit

Abstract

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 γ2L GABA subunit results in an ethanol sensitive and an ethanol‐insensitive form, when combined with α and β 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 γ2L insert is critical for modulation by ethanol but not benzodiazepines, and manipulation of the phosphorylating enzymes in oocytes containing α1β1γ2L 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.