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J Biol Chem, Vol. 273, Issue 10, 5615-5624, March 6, 1998
From the Margaret M. Dyson Vision Research Institute, Department of
Ophthalmology, Cornell University Medical College,
New York, New York 10021
On the basis of sequence homology and structural
similarities, metabotropic glutamate receptors (mGluRs), extracellular
Ca2+-sensing receptor, 
-aminobutyric acid type B
receptor, and pheromone receptors are enlisted in a distinct family
within the larger G protein-coupled receptor superfamily. When
expressed in heterologous systems, group I mGluRs can activate dual
signal transduction pathways, phosphoinositides turnover and cAMP
production. To investigate the structural basis of these coupling
properties, we introduced single amino acid substitutions within the
second and third intracellular loops (i2 and i3) of mGluR1
.
Wild-type and mutant receptors were expressed in human embryonic kidney
293 cells and analyzed for their capacity to stimulate both signaling
cascades. Each domain appeared to be critical for the coupling to
phospholipase C and adenylyl cyclase. Within i2, Thr695,
Lys697, and Ser702 were found to be selectively
involved in the interaction with Gq class subunit(s),
whereas mutation of Pro698 and the deletion
Cys694-Thr695 affected only Gs
coupling. Furthermore, the mutation K690A profoundly altered mGluR1
signaling properties and imparted to the receptor the ability to couple
to the inhibitory cAMP pathway. Within i3, we uncovered two residues,
Arg775 and Phe781, that are crucial for
coupling to both pathways, since their substitution leads to receptor
inactivation.
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