REGULATION OF GABA(A) RECEPTOR FUNCTION BY PROTEIN-KINASE-C PHOSPHORYLATION

GABA(A) receptors possess consensus sequences for phosphorylation by P KC that are located on the presumed intracellular domains of beta and gamma 2 subunits. PKC phosphorylation sites were analyzed using purifi ed receptor subunits and were located on up to 3 serine residues in be ta 1 and gamma 2 subunits. The role of phosphorylation in receptor fun ction was studied using recombinant receptors expressed in kidney cell s and Xenopus oocytes and was compared with native neuronal GABA(A) re ceptors. For recombinant and native GABA(A) receptors, PKC phosphoryla tion caused a reduction in the amplitudes of GABA-activated currents w ithout affecting the time constants for current decay. Selective site- directed mutagenesis of the serine residues reduced the effects of pho rbol esters and revealed that serine 343 in the gamma 2 subunit exerte d the largest effect on the GABA-activated response. These results ind icate that PKC phosphorylation can differentially modulate GABA(A) rec eptor function.