A CLUSTER OF BASIC RESIDUES IN THE CARBOXYL-TERMINAL TAIL OF THE SHORT METABOTROPIC GLUTAMATE-RECEPTOR-1 VARIANTS IMPAIRS THEIR COUPLING TOPHOSPHOLIPASE-C

Among phospholipase C-coupled metabotropic glutamate receptors (mGluRs ), some have a surprisingly long carboxyl-terminal intracellular domai n (mGluR1a, -5a, and -5b), and others have a short one (mGluR1a, -1c, and -1d). All mGluR1 sequences are identical up to 46 residues followi ng the 7th transmembrane domain, followed by 313, 20, 11, and 26 speci fic residues in mGluR1a, mGluR1b, mGluR1c, and mGluR1d, respectively. Several functional differences have been described between the long is oforms (mGluR1a, -5a, and -5b) and the short ones (mGluR1b, -1c, and - 1d). Compared with the long receptors, the short ones induce slower in creases in intracellular Ca2+ are activated by higher concentration of agonists, and do not exhibit constitutive, agonist-independent activi ty, To identify the residues responsible for these functional properti es, a series of truncated, chimeric, and mutated receptors were constr ucted We found that the deletion of the last 19 carboxyl-terminal resi dues in mGluR1c changed its properties into those of mGluR1a. Moreover , the exchange of the long carboxyl-terminal domain of mGluR5a with th at of mGluR1c generated a chimeric receptor that possessed functional properties similar to those of mGluR1c. Mutagenesis of specific residu es within the 19 carboxyl-terminal residues of mGluR1c revealed the im portance of a cluster of 4 basic residues in defining the specific pro perties of this receptor. Since this cluster is part of the sequence c ommon to all mGluR1 variants, we conclude that the long carboxyl-termi nal domain of mGluR1a suppresses the inhibitory action of this sequenc e element.