GLUTAMATE RECEPTORS - BRAIN-FUNCTION AND SIGNAL-TRANSDUCTION

Glutamate receptors are important in neural plasticity, neural develop ment and neurodegeneration. N-methyl-D-aspartate (NMDA) receptors and pha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate rece ptors act as glutamate-gated cation channels, whereas metabotropic rec eptors (mGluRs) modulate the production of second messengers via G pro teins. Molecular studies from our and other laboratories indicated tha t NMDA receptors and mGluRs exist as multiple subunits (NMDAR1 and NMD AR2A-2D) and multiple subtypes (mGluR1-mGluR8). In light of the molecu lar diversity of glutamate receptors, we explored the function and int racellular signaling mechanisms of different members of glutamate rece ptors. In the visual system, retinal bipolar cells receive glutamate t ransmission from photoreceptors and contribute to segregating visual s ignals into ON and OFF pathways. The molecularly cloned mGluR6 is rest rictedly expressed at the postsynaptic site of ON-bipolar cells in bot h rod and cone systems. Gene targeting of mGluR6 results in a loss of ON responses without changing OFF responses and severely impairs detec ting visual contrasts. Since AMPA receptors mediate OFF responses in O FF-bipolar cells, two distinct types of glutamate receptors effectivel y operate for ON and OFF responses. mGluR1 and mGluR5 are both coupled to inositol triphosphate (IP3)/calcium signal transduction with an id entical agonist selectivity. Single-cell intracellular calcium ([Ca2+] (i)) recordings indicated that glutamate evokes a non-oscillatory and oscillatory [Ca2+](i) response in mGluR1-expressing and mGluR5-express ing cells, respectively. This difference results from a single amino a cid substitution, aspartate of mGluR1 or threonine of mGluR5, at the G protein-interacting carboxy-terminal domains. Protein kinase G phosph orylation of the threonine of mGluR5 is responsible for inducing [Ca2](i) oscillations in mGluR5-expressing cells and cultured glial cells. Thus, the two closely related mGluR subtypes mediate diverging intrac ellular signaling in glutamate transmission. (C) 1998 Elsevier Science B.V. All rights reserved.