MODULATION OF GABA(A) RECEPTORS BY TYROSINE PHOSPHORYLATION

gamma-AMINOBUTYRIC acid type-A (GABA(A)) receptors are the major sites of fast synaptic inhibition in the brain, They are presumed to be pen tameric heteroligomers assembled from four classes of subunits with mu ltiple members: alpha (1-6), beta (1-3), gamma (1-3) and delta (1)(1-5 ). Here, GABA(A) receptors consisting of alpha 1, beta 1 and gamma 2L subunits, coexpressed in mammalian cells with the tyrosine kinase vSRC (the transforming gene product of the Rous sarcoma virus), were phosp horylated on tyrosine residues within the gamma 2L and beta 1 subunits . Tyrosine phosphorylation enhanced the whole-cell current induced by GABA. Site-specific mutagenesis of two tyrosine residues within the pr edicted intracellular domain of the gamma 2L subunit abolished tyrosin e phosphorylation of this subunit and eliminated receptor modulation. A similar modulation of GABA(A) receptor function was observed in prim ary neuronal cultures. As GABA(A) receptors are critical in mediating fast synaptic inhibition, such a regulation by tyrosine kinases may th erefore have profound effects on the control of neuronal excitation.