GABAB receptors function as a heteromeric assembly of the subunits GABABR1 and GABABR2

Abstract

The principal inhibitory neurotransmitter GABA (gamma-aminobutyric acid) exerts its effects through two ligand-gated channels, GABA(A) and GABA(C) receptors, and a third receptor, GABA(B) , which acts through G proteins to regulate potassium and calcium channels. Cells heterologously expressing the cloned DNA encoding the GABA(B)R1 protein exhibit high-affinity antagonist-binding sites, but they produce little of the functional activity expected from studies of endogenous GABA(B) receptors in the brain. Here we describe a new member of the GABA(B) polypeptide family, GABA(B)R2, that shows sequence homology to GABA(B)R1. Neither GABA(B)R1 nor GABA(B)R2, when expressed individually, activates GIRK-type potassium channels; however, the combination of GABA(B)R1 and GABA(B)R2 confers robust stimulation of channel activity. Both genes are co-expressed in individual neurons, and both proteins co-localize in transfected cells. Moreover, immunoprecipitation experiments indicate that the two polypeptides associate with each other, probably as heterodimers. Several G-protein-coupled receptors (GPCRs) exist as high-molecular-weight species, consistent with the formation of dimers by these receptors, but the relevance of these species for the functioning of GPCRs has not been established. We have now shown that co-expression of two GPCR structures, GABA(B)R1 and GABA(B)R2, belonging to the same subfamily is essential for signal transduction by GABA(B) receptors.

Surface expression of metabotropic glutamate receptor variants mGluR1a and mGluR1b in transfected HEK293 cells

“…In this receptor, extracellular domains and heptahelical domains of two subunits GB1 and GB2 have to assemble to form a functional receptor complex (Jones et al, 1998;Kaupmann et al, 1998;White et al, 1998). The C-termini are not crucial for G-protein activation by GABAb receptor as truncation of these does not prevent coupling to Gi/o pathway (Pagano et al, 2001).…”

“…The GABAb receptor is formed by subunits GB1 and GB2 that have to assemble in functional complexes (Jones et al, 1998;Kaupmann et al, 1998;White et al, 1998). The carboxyl-termini of the GABAb receptor are involved in quality-control of proper heterodimerization but are not mandatory for G-protein coupling (Pagano et al, 2001).…”

Molecular Targets for Antiepileptic Drug Development

“…The functional receptor is a heteromeric dimer made up of a GABA B1 and GABA B2 subunit 311,312 (FIG. 6).…”

Constitutive, agonist-accelerated, recycling and lysosomal degradation of GABAB receptors in cortical neurons

“…GABA B receptors are heterodimeric G protein-coupled receptors constituted of two different seven-transmembrane proteins termed GABA B1 and GABA B2 (Jones et al, 1998;Kaupmann et al, 1998;Kuner et al, 1999;Martin et al, 1999;Ng et al, 1999;White et al, 1998). Two main variants of GABA B1 that differ in their N-terminal domain are generated by alternative promoter usage (Steiger et al, 2004) and give rise to two GABA B receptor subtypes, GABA B1a /GABA B2 and GABA B1b /GABA B2 .…”