PT - JOURNAL ARTICLE AU - Richard Sullivan AU - Anne Chateauneuf AU - Nathalie Coulombe AU - Lee F. Kolakowski, Jr. AU - Michael P. Johnson AU - Terence E. Hebert AU - Nathalie Ethier AU - Michel Belley AU - Kathleen Metters AU - Mark Abramovitz AU - Gary P. O'Neill AU - Gordon Y. K. Ng TI - Coexpression of Full-Length γ-Aminobutyric Acid<sub>B</sub>(GABA<sub>B</sub>) Receptors with Truncated Receptors and Metabotropic Glutamate Receptor 4 Supports the GABA<sub>B</sub> Heterodimer as the Functional Receptor DP - 2000 May 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 460--467 VI - 293 IP - 2 4099 - http://jpet.aspetjournals.org/content/293/2/460.short 4100 - http://jpet.aspetjournals.org/content/293/2/460.full SO - J Pharmacol Exp Ther2000 May 01; 293 AB - Direct evidence is lacking to show whether the γ-aminobutyric acid (GABA)B gb1-gb2 heterodimer is the signaling form of the receptor. In this study, we tested whether gb1a or gb2 subunits when coexpressed with truncated receptors or metabotropic glutamate receptor mGluR4 could form functional GABA receptors. Coexpression of the ligand binding N-terminal domain of gb1a or the C-terminal portion of gb1a composing the seven-transmembrane segments and intracellular loops with gb2 could not reconstitute functional receptors. We next examined whether mGluR4, which forms homodimers and is structurally related to GABAB, could act as a surrogate coreceptor for gb1 or gb2. The coexpression of mGluR4 and gb1a led to the expression of gb1a monomers on cell surface membranes as determined by immunoblot analysis and flow cytometry. However, mGluR4-gb1a heterodimers were not formed, and membrane-expressed gb1a monomers were not functionally coupled to adenylyl cyclase in human embryonic kidney 293 cells or activated inwardly rectifying potassium (Kir) channels in Xenopusoocytes. Similarly, the coexpression of mGluR4 and gb2 led to nonfunctional GABA receptors. GABA-activated distal signaling events resulted only after the coexpression and heterodimerization of gb1 and gb2. Taken together with the truncated receptor studies, the data suggest that a high degree of structural specificity is required to form the functional GABAB receptor that is a gb1-gb2 heterodimer. The American Society for Pharmacology and Experimental Therapeutics