Abstract
The principal inhibitory neurotransmitter GABA (γ-aminobutyric acid) exerts its effects through two ligand-gated channels, GABAA and GABAC receptors, and a third receptor, GABAB (ref. 1), which acts through G proteins to regulate potassium and calcium channels. Cells heterologously expressing the cloned DNA encoding the GABABR1 protein exhibit high-affinity antagonist-binding sites2, but they produce little of the functional activity expected from studies of endogenous GABAB receptors in the brain. Here we describe a new member of the GABAB polypeptide family, GABABR2, that shows sequence homology to GABABR1. Neither GABABR1 nor GABABR2, when expressed individually, activates GIRK-type potassium channels; however, the combination of GABABR1 and GABABR2 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 receptors3,4,5,6,7, 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, GABABR1 and GABABR2, belonging to the samesubfamily is essential for signal transduction by GABAB receptors.
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Acknowledgements
We thank T. Swayne for use of the confocal microscopy facility at Columbia University; H.-Y. Chang, K. Ogozalek, J. Huang and Y. Wan for support with molecular biology; P. Vaysse for cell biology facilities; C. Forray for advice on membrane fractionation; and S. Rabacchi for helpful hints on protein immunodetection.
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Jones, K., Borowsky, B., Tamm, J. et al. GABAB receptors function as a heteromeric assembly of the subunits GABABR1 and GABABR2. Nature 396, 674–679 (1998). https://doi.org/10.1038/25348
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DOI: https://doi.org/10.1038/25348
