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

Kenneth A. Jones (), Beth Borowsky, Joe A. Tamm, Douglas A. Craig, Margaret M. Durkin, Meng Dai, Wen-Jeng Yao, Mary Johnson, Caryn Gunwaldsen, Ling-Yan Huang, Cheng Tang, Quanrong Shen, John A. Salon, Kelley Morse, Thomas Laz, Kelli E. Smith, Dhanapalan Nagarathnam, Stewart A. Noble, Theresa A. Branchek and Christophe Gerald
Additional contact information
Kenneth A. Jones: Synaptic Pharmaceutical Corporation
Beth Borowsky: Synaptic Pharmaceutical Corporation
Joe A. Tamm: Synaptic Pharmaceutical Corporation
Douglas A. Craig: Synaptic Pharmaceutical Corporation
Margaret M. Durkin: Synaptic Pharmaceutical Corporation
Meng Dai: Synaptic Pharmaceutical Corporation
Wen-Jeng Yao: Synaptic Pharmaceutical Corporation
Mary Johnson: Synaptic Pharmaceutical Corporation
Caryn Gunwaldsen: Synaptic Pharmaceutical Corporation
Ling-Yan Huang: Synaptic Pharmaceutical Corporation
Cheng Tang: Synaptic Pharmaceutical Corporation
Quanrong Shen: Synaptic Pharmaceutical Corporation
John A. Salon: Synaptic Pharmaceutical Corporation
Kelley Morse: Synaptic Pharmaceutical Corporation
Thomas Laz: Synaptic Pharmaceutical Corporation
Kelli E. Smith: Synaptic Pharmaceutical Corporation
Dhanapalan Nagarathnam: Synaptic Pharmaceutical Corporation
Stewart A. Noble: Synaptic Pharmaceutical Corporation
Theresa A. Branchek: Synaptic Pharmaceutical Corporation
Christophe Gerald: Synaptic Pharmaceutical Corporation

Nature, 1998, vol. 396, issue 6712, 674-679

Abstract: 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.

Date: 1998
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DOI: 10.1038/25348

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