Physiological Significance of the extracellular Ca2+ Sensitivity of the Metabotropic Glutamate Receptor

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We previously reported that the metabotropic glutamate receptor R1 a (mGluR1 α) can be activated not only by applying glutamate but also by raising extracellular Ca^<2+> (Ca^<2+>_0) concentration, and that the constant stimulation by Ca^<2+>_0 causes morphological change of transfected Chinese Hamster Ovary (CHO) cells. The physiological role of the Ca^<2+>_0-sensing function of mGluR1 α, however, is not fully clear yet, especially because Ca^<2+> is constitutively present an the extracellular space unlike other neurotransmitters. In this work, we aimed to elucidate the physiological significance of the Ca^<2+>_0-sensing function of mGluR1 α. The effect of mGluR1 α activation by Ca^<2+>_0on the morphological change of CHO cells was mimicked by forskolin. The effect of mGluR1 a activation on the morphological change was suppressed by the inhibitors of adenylate cyclase, protein kinase A (PKA) and MAP kinase kinase (MAPKK), and the effect of forskolin was also decreased by the inhibitors of PKA and MAPKK.These results demonstrate the involvement of cAMP, PKA, MAPKK, MARK pathway in the morphological change. We actually confirmed that the Ca^<2+>_0stimulation of mGluR1 α increased the basal cAMP level of transfected CHO cells. This increase in cAMP was observed even when only the membrane fraction of mGluR1 a transfected CHO cells were used, and the increase was inhibited by anti-Gsα antibody. Taken together, we concl uded that the Ca^<2+>_0-sensing function of mGluR1 a and the continuous stimulation by Ca^<2+>_0 caused the increase in the basal cAMP level by direct coupling with Gs, and triggered the subsequent activation of PKA, MAPKK, and MAPK cascade which resulted in the morphological change of transfected CHO cells.