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0031-6997/08/6004-536-581$7.00
Pharmacol Rev 60:536-581, 2008

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Metabotropic Glutamate 1 Receptor: Current Concepts and Perspectives

Francesco Ferraguti, Luca Crepaldi1 and Ferdinando Nicoletti

Department of Pharmacology, Innsbruck Medical University, Innsbruck, Austria (F.F., L.C.); Department of Human Physiology and Pharmacology, University "La Sapienza," Rome, Italy (F.N.); and I. N. M. Neuromed, Pozzilli, Italy (F.N.)

Abstract
I. Introduction
II. Genomic Organization of the Metabotropic Glutamate 1 Receptor
    A. Chromosomal Localization and Organization of the Metabotropic Glutamate 1 Receptor Gene
    B. Transcriptional Regulation
    C. Alternative Splicing
III. Structural Features of Metabotropic Glutamate 1 Receptors
    A. The Extracellular Domain and the Agonist Binding Site
    B. The Cysteine-Rich Domain
    C. The Heptahelical Transmembrane Domain
    D. Possible Mechanisms of Metabotropic Glutamate 1 Receptor Activation
    E. The Carboxyl-Terminal Domain
IV. Intracellular Coupling of Metabotropic Glutamate 1 receptors
    A. G-Protein Coupling
    B. Signal Transduction Mechanisms
    C. Metabotropic Glutamate 1 Receptor Function and Interacting Proteins
    D. Desensitization and Trafficking
V. Pharmacology
    A. Agonist Pharmacology
    B. Competitive Antagonists
    C. Positive Allosteric Modulators
    D. Noncompetitive Antagonists
VI. Anatomy and Physiology
    A. Cellular and Subcellular Distribution
    B. General Physiological Properties
        1. Distribution and Role of Metabotropic Glutamate 1 Receptors in the Olfactory System.
        2. Distribution and Role of Metabotropic Glutamate 1 Receptors in the Hypothalamus.
        3. Distribution and Role of Metabotropic Glutamate 1 Receptors in the Thalamus.
        4. Distribution and Role of Metabotropic Glutamate 1 Receptors in the Basal Ganglia.
        5. Distribution and Role of Metabotropic Glutamate 1 Receptors in the Hippocampus.
        6. Distribution and Role of Metabotropic Glutamate 1 Receptors in the Cerebellum.
        7. Distribution and Role of Metabotropic Glutamate 1 Receptors in the Spinal Cord.
VII. Implication in Diseases
    A. Cerebellar Ataxia
    B. Extrapyramidal Motor Dysfunctions
    C. Fear and Anxiety
    D. Mood Disorders
    E. Excitotoxicity
    F. Epilepsy and Seizures
    G. Pain
    H. Role of Metabotropic Glutamate 1 Receptors in Melanoma Development
VIII. Perspectives and Directions for Future Studies
Almost 25 years after the first report that glutamate can activate receptors coupled to heterotrimeric G-proteins, tremendous progress has been made in the field of metabotropic glutamate receptors. Now, eight members of this family of glutamate receptors, encoded by eight different genes that share distinctive structural features have been identified. The first cloned receptor, the metabotropic glutamate (mGlu) receptor mGlu1 has probably been the most extensively studied mGlu receptor, and in many respects it represents a prototypical subtype for this family of receptors. Its biochemical, anatomical, physiological, and pharmacological characteristics have been intensely investigated. Together with subtype 5, mGlu1 receptors constitute a subgroup of receptors that couple to phospholipase C and mobilize Ca2+ from intracellular stores. Several alternatively spliced variants of mGlu1 receptors, which differ primarily in the length of their C-terminal domain and anatomical localization, have been reported. Use of a number of genetic approaches and the recent development of selective antagonists have provided a means for clarifying the role played by this receptor in a number of neuronal systems. In this article we discuss recent advancements in the pharmacology and concepts about the intracellular transduction and pathophysiological role of mGlu1 receptors and review earlier data in view of these novel findings. The impact that this new and better understanding of the specific role of these receptors may have on novel treatment strategies for a variety of neurological and psychiatric disorders is considered.

Address correspondence to: Dr. Francesco Ferraguti, Department of Pharmacology, Innsbruck Medical University, Peter-Mayr Strasse 1a, Innsbruck A-6020, Austria. E-mail: francesco.ferraguti{at}i-med.ac.at






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