THE 2ND INTRACELLULAR LOOP OF METABOTROPIC GLUTAMATE-RECEPTOR-1 COOPERATES WITH THE OTHER INTRACELLULAR DOMAINS TO CONTROL COUPLING TO G-PROTEINS

Metabotropic glutamate receptors (mGluR) share no sequence homology wi th any other G-protein-coupled receptors (GPCRs). The characterization of their G-protein coupling domains will therefore help define the ge neral rules for receptor-G-protein interaction. To this end, the intra cellular domains of mGluR3 and mGluR1, receptors coupled negatively to adenylyl cyclase and positively to phospholipase C, respectively, wer e systematically exchanged. The ability of these chimeric receptors to induce Ca2+ signals were examined in Xenopus oocytes and HEK 293 cell s. The chimeric receptors that still possessed the second intracellula r loop (i2) of mGluR3 induced little or no Ca2+ signals, even though t hese proteins were targeted correctly to the plasma membrane. Consiste nt Ca2+ signals could be recorded only with chimeric mGluR3 receptors that contains i2 and at least one other intracellular domain of mGluR1 . However, most intracellular domains of mGluR3 have to be replaced by their mGluR1 equivalent to produce optimal coupling to G protein. The se observations indicate that i2 of mGluR1 is a critical element in de termining the transduction mechanism of this receptor. These results s uggest that i2 of mGluRs may play a role similar to i3 of most other G PCRs in the specificity of coupling to the G-proteins. Moreover, as in many other GPCRs, our data revealed cooperation between the different mGluR intracellular domains to control efficient coupling to G-protei ns.