Biochemical Journal

Review

Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors

Emmanuel HERMANS, R. A. John CHALLISS

Abstract

In 1991 a new type of G-protein-coupled receptor (GPCR) was cloned, the type 1a metabotropic glutamate (mGlu) receptor, which, despite possessing the defining seven-transmembrane topology of the GPCR superfamily, bore little resemblance to the growing number of other cloned GPCRs. Subsequent studies have shown that there are eight mammalian mGlu receptors that, together with the calcium-sensing receptor, the GABAB receptor (where GABA is γ-aminobutyric acid) and a subset of pheromone, olfactory and taste receptors, make up GPCR family C. Currently available data suggest that family C GPCRs share a number of structural, biochemical and regulatory characteristics, which differ markedly from those of the other GPCR families, most notably the rhodopsin/family A GPCRs that have been most widely studied to date. This review will focus on the group I mGlu receptors (mGlu1 and mGlu5). This subgroup of receptors is widely and differentially expressed in neuronal and glial cells within the brain, and receptor activation has been implicated in the control of an array of key signalling events, including roles in the adaptative changes needed for long-term depression or potentiation of neuronal synaptic connectivity. In addition to playing critical physiological roles within the brain, the mGlu receptors are also currently the focus of considerable attention because of their potential as drug targets for the treatment of a variety of neurological and psychiatric disorders.

  • Homer proteins
  • protein kinase C
  • receptor desensitization
  • receptor phosphorylation
  • signal transduction

Footnotes

  • Abbreviations used: AMPA, α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid; BAY36-7620, (3aS,6aS)-6a-naphtalen-2-ylmethyl-5-methyliden-hexahydrocyclopental[c]-furan-1-one; BHK, baby hamster kidney; [Ca2+]e, extracellular Ca2+ concentration; CaR, Ca2+-sensing receptor; CHO, Chinese hamster ovary; CPCCOEt, 7-(hydroxylimino)cyclopropa-[b]chromen-1a-carboxylate; e2 loop (etc.), second extracellular loop (etc.); ERK, extracellular-signal-regulated protein kinase; EVH1, Drosophila Enabled, mammalian VASP, Wiscott–Aldridge syndrome protein homology domain; GABA, γ-aminobutyric acid; GPCR, G-protein-coupled receptor; GRK, G-protein-coupled receptor kinase; HEK, human embryonic kidney; i3 loop (etc.), third intracellular loop (etc.); iGlu receptor, ionotropic glutamate receptor; LIVBP, leucine/isoleucine/valine binding protein; MAPK, mitogen-activated protein kinase; mGlu receptor, metabotropic glutamate receptor; MPEP, 2-methyl-6-(phenylethynyl)pyridine; NMDA, N-methyl-d-aspartate; PDZ domain, postsynaptic density-95, Discs-large, Zona occludens-1 domain; PKC, protein kinase C; PLC, phospholipase C; PSD, postsynaptic density; PTx, pertussis toxin; RGS, regulator of G-protein signalling; sBim receptor, salmon bifunctional receptor; TM7 domain (etc.), transmembrane domain 7 (etc.); VOCC, voltage-operated Ca2+ channel.