FUNCTIONAL MODULATION OF GABA(A) RECEPTORS BY CAMP-DEPENDENT PROTEIN-PHOSPHORYLATION

Gamma-aminobutyric acid(A) (GABA(A)) receptors are ligand-gated ion channels that mediate inhibitory synaptic transmission in the central nervous system. The role of protein phosphorylation in the modulation of GABA(A) receptor function was examined with cells transiently transfected with GABA(A) receptor subunits. GABA(A) receptors consisting of the alpha-1 and beta-1 or the alpha-1, beta-1, and gamma-2, subunits were directly phosphorylated on the beta-1 subunit by adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase (PKA). The phosphorylation decreased the amplitude of the GABA response of both receptor types and the extent of rapid desensitization of the GABA(A) receptor that consisted of the alpha-1 and beta-1 subunits. Site-specific mutagenesis of the serine residue phosphorylated by PKA completely eliminated the PKA phosphorylation and modulation of the GABA(A) receptor. In primary embryonic rat neuronal cell cultures, a similar regulation of GABA(A) receptors by PKA was observed. These results demonstrate that the GABA(A) receptor is directly modulated by protein phosphorylation and suggest that neurotransmitters or neuropeptides that regulate intracellular cAMP levels may modulate the responses of neurons to GABA and consequently have profound effects on synaptic excitability.