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Vol. 59, Issue 1, 46-53, January 2001
Departments of Ophthalmology and Visual Sciences (C.R., S.D.),
Anatomy and Neurobiology (C.R., J.K.M., K.L.O.), Neurology (K.H.,
M.P.G.), and Psychiatry (S.M.), Washington University School of
Medicine, St. Louis, Missouri; and Banyu Tsukaba Research Institute,
Tsukaba, Japan (Y.T.)
Some, perhaps all, G protein-coupled receptors form homo- or
heterodimers. We have shown that metabotropic glutamate receptors are
covalent dimers, held together by one or more disulfide bonds near the
N terminus. Here we report how mutating cysteines in this region affect
dimerization and function. Covalent dimerization is preserved when
cysteines 57, 93, or 99 are mutated but lost with replacement at 129. Coimmunoprecipitation under nondenaturing conditions indicates that the
C[129]S mutant receptor remains a dimer, via noncovalent
interactions. Both C[93]S and C[129]S bind
[3H]quisqualate, whereas binding to C[57]S or C[99]S
mutants is absent or greatly attenuated. The C[93]S and C[129]S
receptors have activity similar to wild-type when assayed by fura-2
imaging of intracellular calcium in human embryonic kidney cells or
electrophysiologically in Xenopus laevis oocytes. In
contrast, C[57]S or C[99]S are less active in both assays but do
respond with higher glutamate concentrations in the oocyte assay. These
results demonstrate that 1) covalent dimerization is not critical for
mGlu5 binding or function; 2) mGlu5 remains a
noncovalent dimer even in the absence of covalent dimerization; and 3)
high-affinity binding requires Cys-57 and Cys-99.
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