Cyclic AMP–dependent protein kinase phosphorylation facilitates GABAB receptor–effector coupling

Abstract

GABA (γ-aminobutyric acid)_B receptors are heterodimeric G protein–coupled receptors that mediate slow synaptic inhibition in the central nervous system. Here we show that the functional coupling of GABA_BR1/GABA_BR2 receptors to inwardly rectifying K⁺ channels rapidly desensitizes. This effect is alleviated after direct phosphorylation of a single serine residue (Ser892) in the cytoplasmic tail of GABA_BR2 by cyclic AMP (cAMP)–dependent protein kinase (PKA). Basal phosphorylation of this residue is evident in rat brain membranes and in cultured neurons. Phosphorylation of Ser892 is modulated positively by pathways that elevate cAMP concentration, such as those involving forskolin and β-adrenergic receptors. GABA_B receptor agonists reduce receptor phosphorylation, which is consistent with PKA functioning in the control of GABA_B-activated currents. Mechanistically, phosphorylation of Ser892 specifically enhances the membrane stability of GABA_B receptors. We conclude that signaling pathways that activate PKA may have profound effects on GABA_B receptor–mediated synaptic inhibition. These results also challenge the accepted view that phosphorylation is a universal negative modulator of G protein–coupled receptors.