Padgett Claire L, Slesinger Paul A
Peptide Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
Adv Pharmacol. 2010;58:123-47. doi: 10.1016/S1054-3589(10)58006-2.
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.
γ-氨基丁酸B（GABA(B)）受体已被发现，在调节大脑中的膜兴奋性和突触传递方面发挥关键作用。GABA(B)受体是一种G蛋白偶联受体（GPCR），它与一部分G蛋白（对百日咳毒素敏感的Gi/o家族）相关联，这些G蛋白进而调节特定的离子通道并触发环磷酸腺苷（cAMP）级联反应。在这篇综述中，我们描述了GABA(B)受体、其效应器以及在大脑中介导GABA(B)受体功能的相关蛋白之间的关系。我们讨论了GABA(B)受体的一个独特特征，即需要异源二聚化才能产生功能性受体，以及越来越多的证据表明GABA(B)受体构成了一个大分子信号异源复合物，这对于受体的有效靶向和功能至关重要。在这个复合物中，GABA(B)受体与调节电压门控钙（Ca(2+)，Ca(V)）通道、G蛋白激活的内向整流钾（GIRK）通道和腺苷酸环化酶的Gi/o G蛋白特异性结合。大量研究表明，脂筏、支架蛋白、受体中的靶向基序以及G蛋白信号调节（RGS）蛋白也对GABA(B)受体的功能有贡献，并影响诸如受体转运和活性依赖性脱敏等细胞过程。大脑中GABA(B)受体的这种复杂调节可能为在神经系统的正常和疾病状态下调节GABA依赖性抑制提供新的途径。
