Shigetada Nakanishia,*, Yoshiaki Nakajimaa , Masayuki Masua, Yoshiki Uedaa, Kiyoshi Nakaharaa, Dai Watanabea, Shun Yamaguchia, Shigeki Kawabatab, Masamichi Okadab
aDepartment of Biological Sciences, Kyoto University Faculty of Medicine, Yoshida, Sakyo-ku, Kyoto 606, Japan, bNeuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 305, Japan
Glutamate receptors are important in neural plasticity, neural development and neurodegeneration. N-methyl-D-aspartate (NMDA) receptors and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors act as glutamate-gated cation channels, whereas matabotropic receptors (mGluRs) modulate the production of second messengers via G proteins. Molecular studies from our other laboratories indicated NMDA receptors and MGluRs exist as multiple subunits (NMDAR1 and NMDAR2A-2D) and multiple subtypes (mG1ur1-mG1uR8). In light of the molecular diversity of glutamate receptors, we explored the function and intracellular signaling mechanisms of different members of glutamate receptors. In the visual system, retinal bipolar cells receive glutamate transmission from photoreceptors and contribute to segregating visual signals into ON and OFF pathways. The molecularly cloned mG1uR6 is restrictedly expressed at the postsynaptic site of ON-bipolar cells in both rod and cone systems. Gene targeting of mG1uR6 results in a loss of ON responses without changing OFF responses and severely impairs detecting visual constrasts. Since AMPA receptors mediate OFF responses in OFF-bipolar cells, two distinct types of glutamate receptors effectively operate for ON and OFF responses. mG1uR1 and mG1uR5 are both coupled to inositol triphosphate (IP3)/calcium signal transduction with an identical agonist selectivity. Single-cell intracellular calcium ([Ca2+]i) recordings indicated that glutamate evokes a non-oscillatory and oscillatory [Ca2+]i response in mG1uR1-expressing and mG1uR5-expressing cells, respectively. This difference results from a single amino acid substitution, aspartate of mG1uR1 or threonine of mG1uR5, at the G protein-interacting carboxy-terminal domains. Protein kinase C phosphorylation of the threonine of mG1uR5 is responsible for inducing [Ca2+]i oscillations in mGluR5-expessing cells and cultured glial cells. Thus, the two closely related MG1uR subtypes mediate diverging intracellular signaling in glutamate transmission.
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Brain Research Reviews 26 (1998)
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