Functional Modulation of GABA_A Receptors by cAMP-Dependent Protein Phosphorylation
Abstract
γ-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 α_1 and β_1 or the α_1, β_1, and γ_2 subunits were directly phosphorylated on the β_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 α_1 and β_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.
- Publication:
-
Science
- Pub Date:
- July 1992
- DOI:
- 10.1126/science.1323140
- Bibcode:
- 1992Sci...257..661M