Glutamate receptors: brain function and signal transduction1

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Abstract

Glutamate receptors are important in neural plasticity, neural development and neurodegeneration. N-methyl-d-aspartate (NMDA) receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors act as glutamate-gated cation channels, whereas metabotropic receptors (mGluRs) modulate the production of second messengers via G proteins. Molecular studies from our and other laboratories indicated that NMDA receptors and mGluRs exist as multiple subunits (NMDAR1 and NMDAR2A-2D) and multiple subtypes (mGluR1–mGluR8). 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 mGluR6 is restrictedly expressed at the postsynaptic site of ON-bipolar cells in both rod and cone systems. Gene targeting of mGluR6 results in a loss of ON responses without changing OFF responses and severely impairs detecting visual contrasts. Since AMPA receptors mediate OFF responses in OFF-bipolar cells, two distinct types of glutamate receptors effectively operate for ON and OFF responses. mGluR1 and mGluR5 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 mGluR1-expressing and mGluR5-expressing cells, respectively. This difference results from a single amino acid substitution, aspartate of mGluR1 or threonine of mGluR5, at the G protein-interacting carboxy-terminal domains. Protein kinase C phosphorylation 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 intracellular signaling in glutamate transmission.

Introduction

Glutamate receptors mediate most excitatory neurotransmission in the brain and play an important role in neural plasticity, neural development and neurodegeneration 1, 2, 3, 4. Glutamate receptors are categorized into two distinct groups of receptors termed ionotropic and metabotropic glutamate receptors 5, 6, 7. The ionotropic receptors are subdivided into NMDA receptors and AMPA/kainate receptors, both of which contain glutamate-gated, cation-specific ion channels 4, 6. The mGluRs are coupled to intracellular signal transduction via G proteins 7, 8. We cloned and characterized the NMDA receptors and mGluRs with the aid of our functional cloning strategy that combines electrophysiology and a Xenopus oocyte expression system 5, 9, 10. Both receptors exist as diverse members of the receptor families 4, 6, 7, 8(Fig. 1). The NMDA receptors consist of two distinct types of subunits 4, 6: NMDAR1 is a fundamental subunit that possesses all properties characteristic of the NMDA receptor–channel complex. NMDAR2A-2D are modulatory subunits that have no NMDA receptor activity but potentiate and differentiate the NMDA receptor activity in heteromeric formation with NMDAR1. The mGluRs consist of eight different subtypes (mGluR1–mGluR8) 7, 8. The eight subtypes of the mGluR family are classified into three groups according to their sequence similarities, signal transduction mechanisms and agonist selectivities 7, 8. In the heterologous expression system, mGluR1 and mGluR5 are coupled to IP3/[Ca2+]i signal transduction. All other six subtypes are linked to the inhibitory cAMP cascade, but these subtypes are subdivided into two groups by their distinct agonist selectivities. On the basis of our knowledge of the molecular diversity of glutamate receptors, it is important to explore physiological roles of individual receptor subtypes or subunits in brain function. This article deals with distinct functions and signal transduction mechanisms of different subtypes of the mGluR family.

Section snippets

mGluR6 in visual transmission

In the retina, photoreceptors receive visual inputs and transmit visual signals to bipolar cells through glutamate transmission 11, 12. The detection of visual contrasts is a key processing of visual transmission, and this discrimination occurs at the level of bipolar cells by segregating the visual signals into ON-center and OFF-center pathways [13]. Photoreceptors hyperpolarize by light exposure and reduce glutamate release. In turn, ON- and OFF-bipolar cells depolarize and hyperpolarize,

Distinct intracellular calcium responses of mGluR1 and mGluR5

mGluR1 and mGluR5 are commonly coupled to the IP3/[Ca2+]i signal transduction and show a virtually identical responsiveness to various selective agonists 5, 23. Although these two closely related mGluR subtypes exhibit distinct expression patterns in many brain regions 9, 23, their functional difference remained elusive. We established permanent NIH3T3 and HEK293 cell lines, each expressing either mGluR1 or mGluR5 by cDNA transfection [24]. In these cells, single-cell [Ca2+]i recording

Acknowledgements

This work was partly supported by the Ministry of Education, Science and Culture of Japan, the Ministry of Health and Welfare of Japan, the Uehara Memorial Foundation and the Sankyo Foundation of Life Science.

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