Adjacent phosphorylation sites on GABAA receptor β subunits determine regulation by cAMP-dependent protein kinase

Abstract

Activation of cAMP-dependent protein kinase (PKA) can enhance or reduce the function of neuronal GABA_A receptors, the major sites of fast synaptic inhibition in the brain. This differential regulation depends on PKA-induced phosphorylation of adjacent conserved sites in the receptor β subunits. Phosphorylation of β3 subunit-containing receptors at S408 and S409 enhanced the GABA-activated response, whereas selectively mutating S408 to alanine converted the potentiation into an inhibition, comparable to that of β1 subunits, which are phosphorylated solely on S409. These distinct modes of regulation were interconvertible between β1 and β3 subunits and depended upon the presence of S408 in either subunit. In contrast, β2 subunit-containing receptors were not phosphorylated or affected by PKA. Differential regulation by PKA of postsynaptic GABA_A receptors containing different β subunits may have profound effects on neuronal excitability.