Trends in Pharmacological Sciences
Current AwarenessGABAB receptors – the first 7TM heterodimers
Section snippets
Cloning of the first GABAB receptors
Given the clinical and physiological importance of the GABAB receptor, many attempts at its characterization at the molecular level have been made. Eventually, the development of the high-affinity antagonist [125I]CGP64213 allowed the isolation of the GABABR1a cDNA using radioligand binding2. Subsequently, the N-terminal splice variant GABABR1b, which shares ligand binding and effector domains with GABABR1a, was isolated. The cloning of GABAB receptors revealed extended sequence similarity with
GABAB receptors are heterodimers
The publication of the GABABR1 primary sequence in 1997 (Ref. 2) led to the discovery of a related gene using database searching techniques. This gene, GABABR2, exhibits 35% sequence homology to GABABR1 and the same overall topology as other members of Family ‘C’ GPCRs. Efforts to express functionally this second gene also met largely with failure. There were several lines of evidence to suggest that the functional form of the GABAB receptor might be formed from co-expression of GABABR1 and GABA
Agonist activation of the receptor
Co-expression of GABABR1 and GABABR2 enabled robust coupling to GIRKs (Fig. 1), stimulation of 35[S]GTPγS binding and inhibition of forskolin-stimulated cAMP accumulation. All responses displayed agonist and antagonist pharmacology similar to that previously reported for GABAB receptors in rat brain. Thus, it is likely that the poor surface expression of GABABR1 (4, 11) accounts for its weak cellular responses given that co-expression of GABABR2 promotes the expression of the heterodimer on the
Dimerization of GPCRs
If GABABR1 and GABABR2 can function as individual receptors, how do they behave in the heterodimeric form of the receptor? Both GABABR1 and GABABR2 contain the domain in the N-terminal extracellular region related to the bacterial periplasmic binding proteins, which bind amino acids15, 16 (see Fig. 2). It has been proposed that these domains form two distinct globular regions that close on agonist binding14. Multiple agonist binding to the dimer could potentially lead to co-operative binding,
Relevance of heterodimers to GABAB receptor subtypes
Evidence supports the existence of pharmacological subtypes of GABAB receptors24. At our current level of understanding, however, the dimerization phenomenon does not provide an explanation for these receptor subtypes. Although there appears to be multiple splice variants of GABABR1 and GABABR2, no differences in pharmacology have so far been reported5. It is possible that monomeric forms of GABABR1 and GABABR2 represent subtypes distinct from each other and the heterodimer. Detailed
Glossary
Chemical names
- CGP64213:
- 3-{1-(r)-[2-(s)-hydroxy-3-(hydroxy-{5-[3-(4-hydroxy-3-iodo-phenyl)-propionylamino]-pentyl}-phosphinoyl)-propyl-amino]-ethyl}-benzoic acid
- CGP71872:
- 3-[1-(r)-(3-{[5-(4-azido-2-hydroxy-5-iodo-benzoylamino)-pentyl]-hydroxy-phosphinoyl}-2-(s)-hydroxy-propyl-amino)-ethyl]-benzoic acid
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