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Vol. 293, Issue 2, 460-467, May 2000
-Aminobutyric AcidB
(GABAB) Receptors with Truncated Receptors and Metabotropic
Glutamate Receptor 4 Supports the GABAB Heterodimer as the
Functional Receptor1
Departments of Biochemistry, Molecular Biology and Chemistry, Merck
Frosst Center for Therapeutic Research, Kirkland, Quebec, Canada (R.S.,
A.C., N.C., M.B., K.M., M.A., G.P.O., G.Y.K.N.); Departments of
Pharmacology and Biochemistry, University of Texas Health Science
Center at San Antonio, San Antonio, Texas (L.F.K., M.P.J.); and
Institut de Cardiologie de Montreal, Research Center, Montreal Heart
Institute, Montreal, Quebec, Canada (T.E.H., N.E.)
Direct evidence is lacking to show whether the 
-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 Xenopus
oocytes. 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.
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