Structure of GABA_B Receptors

Abstract

It is close to 20 years since the term GABA_B was first introduced to define a metabotropic GABA receptor with a pharmacological profile distinct from that of the ioHill and Bowery 1981). It was subsequently shown that binding of agonists to GABA_B receptors is sensitive to guanyl nucleotides, indicating that GABA_B receptors are coupled to G-proteins. Many of the physiological roles of GABA_B receptors can be attributed to the regulation of G-protein gated Ca²⁺ and K⁺ channels (Lüscher et al. 1997; Poncer et al. 1997; Slesinger et al. 1997; Wu and Saggau 1997). Accordingly presynaptic GABA_B receptor influence neurotransmission by suppression of neurotransmitter and neuropeptide release, presumably by diminution of a Ca²⁺ conductance. A Ca²⁺ independent interaction of GABA_B receptors with the presynaptic secretion machinery was also proposed (Capogna et al. 1996). Postsynaptic GABA_B receptors hyperpolarize neurons by activating an outward K⁺ current that underlies the late inhibitory postsynaptic potentials (IPSPs). Characteristically the late IPSP is slower in onset and has a prolonged duration as compared to the fast IPSP, which derives from the Cl⁻-permeable GABA_A receptors. Recent studies indicate that inwardly rectifying K⁺ channels of the Kir3 type (formerly GIRK) are prominent effectors of postsynaptic GABA_B receptors. For example, the late IPSP evoked by L-baclofen, a selective GABA_B receptor agonist, is largely absent in Kir3.2 knockout mice (Lüscher et al. 1997).