GABAB-receptor subtypes assemble into functional heteromeric complexes

Abstract

B-type receptors for the neurotransmitter GABA (gamma-aminobutyric acid) inhibit neuronal activity through G-protein-coupled second-messenger systems, which regulate the release of neurotransmitters and the activity of ion channels and adenylyl cyclase. Physiological and biochemical studies show that there are differences in drug efficiencies at different GABA(B) receptors, so it is expected that GABA(B)-receptor (GABA(B)R) subtypes exist. Two GABA(B)-receptor splice variants have been cloned (GABA(B)R1a and GABA(B)R1b), but native GABA(B) receptors and recombinant receptors showed unexplained differences in agonist-binding potencies. Moreover, the activation of presumed effector ion channels in heterologous cells expressing the recombinant receptors proved difficult. Here we describe a new GABA(B) receptor subtype, GABA(B)R2, which does not bind available GABA(B) antagonists with measurable potency. GABA(B)R1a, GABA(B)R1b and GABA(B)R2 alone do not activate Kir3-type potassium channels efficiently, but co-expression of these receptors yields a robust coupling to activation of Kir3 channels. We provide evidence for the assembly of heteromeric GABA(B) receptors in vivo and show that GABA(B)R2 and GABA(B)R1a/b proteins immunoprecipitate and localize together at dendritic spines. The heteromeric receptor complexes exhibit a significant increase in agonist- and partial-agonist-binding potencies as compared with individual receptors and probably represent the predominant native GABA(B) receptor. Heteromeric assembly among G-protein-coupled receptors has not, to our knowledge, been described before.

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).…”

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 .…”

L’hétérodimérisation des récepteurs couplés aux protéines G

“…Chez l'homme, GABA B reste un cas modèle du phénomène de dimérisation car celui-ci est nécessaire au fonctionnement du récepteur. Le récepteur est formé de deux sous-unités, GABA B1 et GABA B2 [23][24][25]. En raison de la présence d'un motif de rétention au niveau de sa partie carboxy-terminale, la sous-unité GABA B1 est piégée dans le réticulum endoplasmique (RE).…”