Constitutive tyrosine phosphorylation of the GABA(A) receptor gamma 2 subunit in rat brain

GABA(A) receptors are the major sites of fast synaptic inhibition in the br ain, where they are predominantly composed of alpha, beta and gamma2 subuni ts. A role for direct tyrosine phosphorylation of residues 365 and 367 (Y36 5/367) within the intracellular domain of the gamma2 subunit has been sugge sted to be important in modulating GABA(A) receptor function. based on the stud of recombinant receptors. To address the relevance of these observatio ns for neuronal GABA(A) receptors we have studied the phosphorylation of th e gamma2 subunit in the brain. In adult rat brain the gamma2 subunit is pho sphorylated on tyrosine residues, including Y365/367 as defined using a pho sphospecific antisera. In cultured cortical neurones, phosphorylation of Y3 65/367 is highly regulated and was only evident upon inhibition of tyrosine phosphatases. We also establish that the tyrosine kinase Src is capable of specifically interacting with the intracellular domains of receptor and ga mma2 subunits. This may specifically localise tyrosine kinase activity to G ABA(A), receptors, facilitating rapid receptor tyrosine phosphorylation upo n kinase activation. Together our results suggests that tyrosine phosphorylation of the gamma2 s ubunit, possibly by closely associated Src. may be a dynamic mechanism for regulating GABA(A) receptor function in the brain. (C) 2001 Elsevier Scienc e Ltd. All rights reserved.