gamma-aminobutyric acid type B receptor and related proteins, member of the class C family of seven-transmembrane G protein-coupled receptors
The type B receptor for gamma-aminobutyric acid, GABA-B, is activated by its endogenous ligand GABA, the principal inhibitory neurotransmitter. The functional GABA-B receptor is an obligatory heterodimer composed of two related subunits, GABA-B1, which is primarily involved in GABA ligand binding, and GABA-B2, which is responsible for both G-protein coupling and trafficking of the heterodimer to the plasma membrane. Activation of GABA-B couples to G(i/o)-type G proteins, which in turn modulate three major downstream effectors: adenylate cyclase, voltage-sensitive Ca2+ channels, and inwardly-rectifying K+ channels. Consequently, GABA-B receptor produces slow and sustained inhibitory responses by decreased neurotransmitter release via inhibition of Ca2+ channels and by postsynaptic hyperpolarization via the activation of K+ channels through the G-protein beta-gamma dimer. The GABA-B is expressed in both pre- and postsynaptic sites of glutamatergic and GABAergic neurons in the brain where it regulates synaptic activity. Thus, the GABA-B receptor agonist, baclofen, is used to treat muscle tightness and cramping caused by spasticity in multiple sclerosis patients. Moreover, GABA-B antagonists improves cognitive performance in mammals, while GABA-B agonists suppress cognitive behavior. In most of the class C family members, the extracellular Venus-flytrap domain in the N-terminus is connected to the seven-transmembrane (7TM) via a cysteine-rich domain (CRD). However, in the GABA-B receptor, the CRD is absent in both subunits and the Venus-flytrap ligand-binding domain is directly connected to the 7TM via a 10-15 amino acids linker, suggesting that GABA-B receptor may utilize a different activation mechanism. Also included in this group are orphan receptors, GPR156 and GPR158, which are closely related to the GABA-B receptor family.
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