GABA _B receptor coupling to G-proteins and ion channels

GABA _B receptors have been found to play a key role in regulating membrane excitability and synaptic transmission in the brain. The GABA _B receptor is a G-protein coupled receptor (GPCR) that associates with a subset of G-proteins (pertussis toxin sensitive Gi/o family), that in turn regulate specific ion channels and trigger cAMP cascades. In this review, we describe the relationships between the GABA _B receptor, its effectors and associated proteins that mediate GABA _B receptor function within the brain. We discuss a unique feature of the GABA _B receptor, the requirement for heterodimerization to produce functional receptors, as well as an increasing body of evidence that suggests GABA _B receptors comprise a macromolecular signaling heterocomplex, critical for efficient targeting and function of the receptors. Within this complex, GABA _B receptors associate specifically with Gi/o G-proteins that regulate voltage-gated Ca ²⁺ (Ca _V ) channels, G-protein activated inwardly rectifying K ⁺ (GIRK) channels, and adenylyl cyclase. Numerous studies have revealed that lipid rafts, scaffold proteins, targeting motifs in the receptor, and regulators of G-protein signaling (RGS) proteins also contribute to the function of GABA _B receptors and affect cellular processes such as receptor trafficking and activity-dependent desensitization. This complex regulation of GABA _B receptors in the brain may provide opportunities for new ways to regulate GABA-dependent inhibition in normal and diseased states of the nervous system.