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Published online before print July 17, 2003

0031-6997/03/5503-509-550$7.00
Pharmacol Rev 55:509-550, 2003

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Molecular Mechanisms and Therapeutical Implications of Intramembrane Receptor/Receptor Interactions among Heptahelical Receptors with Examples from the Striatopallidal GABA Neurons

Luigi F. Agnati1, Sergi Ferré, Carme Lluis, Rafael Franco and Kjell Fuxe

University of Modena, Modena, Italy; National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland; University of Barcelona, Barcelona, Spain; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden

Abstract
I. Experimental Evidence on Protein/Protein Interactions Involving G Protein-Coupled Receptors in the Central Nervous System
    A. Early Indications for Intramembrane Receptor/Receptor Interactions Involving G Protein-Coupled Receptors
    B. G Protein-Coupled Receptors Homo- and Heteromerization
        1. Homomerization of G Protein-Coupled Receptors.
        2. Heteromeric Complexes Involving G Protein-Coupled Receptors.
            a. The GABAB Receptor Heterodimer.
            b. Heteromerization of {delta} and {kappa} Opioid Receptors and of µ and {delta} Opioid Receptors.
            c. The Serotonin 5-HT1D/5-HT1B Receptor Heteromer.
            d. The Dopamine D2/D3 Receptor Heteromer.
            e. The Somatostatin SSTR5/SSTR1 Receptor Heteromer.
            f. The Somatostatin SSTR5 and Dopamine D2 Heteromeric Receptor Complex.
            g. The Adenosine A1 and Dopamine D1 Heteromeric Receptor Complex.
            h. The Metabotropic Glutamate mGluR1{alpha} and Adenosine A1 Heteromeric Receptor Complex.
            i. The Purinergic P2Y1 and Adenosine A1 Heteromeric Receptor Complex.
            j. The Adenosine A2A and Dopamine D2 Heteromeric Receptor Complex.
            k. The Metabotropic Glutamate mGlu5 and Adenosine A2A Heteromeric Receptor Complex.
            l. The Bradykinin B2 and Angiotensin AT1 Heteromeric Receptor Complex.
            m. Other Heteromeric G Protein-Coupled Receptor Complexes.
    C. Direct Protein/Protein Interactions between G Protein-Coupled Receptors and Multisubunit Ligand-Gated Ion Channels
    D. Oligomeric Complexes Containing G Protein-Coupled Receptors and Receptor Tyrosine Kinases
    E. Oligomeric Complexes Containing G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins
        1. Receptor Activity-Modifying Transmembrane Proteins.
            a. The Calcitonin Receptor Family/RAMP1-3 Heteromeric Complexes.
            b. The Dopamine D1 Receptor/Calcyon Heteromeric Complex.
        2. Receptor Activity-Modifying Cytosolic Proteins.
            a. The Adenosine A1 Receptor and Adenosine Deaminase Heteromeric Complex.
            b. The Adenosine A1 Receptor and hsc73 Heteromeric Complex.
II. On the Functional Implications of Receptor/Receptor Interactions
    A. The Context of the Present Discussion
    B. Structural Basis of Receptor Function
        1. Conformational Diversity.
        2. Oligomeric Diversity: The Receptor Mosaic
        3. The Role of the Receptor Mosaic in Learning and Memory.
    C. Communication Processes in the Cell
    D. Receptor/Receptor Interactions in the Striatopallidal GABA Neurons: Implications for Parkinson's Disease, Schizophrenia, and Drug Addiction
        1. Localization of Adenosine A2A, Dopamine D2, and Glutamate Metabotropic mGluR5 Receptors in the GABA Striatopallidal Neuron.
        2. Interactions between Adenosine A2A, Dopamine D2, and Glutamate Metabotropic mGluR5 Receptors in the GABA Striatopallidal Neuron: Biochemical-Cellular Level.
        3. Interactions between Adenosine A2A, Dopamine D2, and Glutamate Metabotropic mGluR5 Receptors in the GABA Striatopallidal Neuron: Physiological-Behavioral Level.
        4. Interactions between Adenosine, Dopamine, and Glutamate Metabotropic Receptors in the GABAergic Striatoentopeduncular and Striatonigral Neurons.
III. Implications of Receptor/Receptor Interactions for Drug Development
    A. The Ground for Novel Therapeutical Interventions
    B. Theoretical Strategies to Target Receptor Complexes
    C. Possible Targets for Drugs Acting on Heteromeric Receptor Complexes
The molecular basis for the known intramembrane receptor/receptor interactions among G protein-coupled receptors was postulated to be heteromerization based on receptor subtype-specific interactions between different types of receptor homomers. The discovery of GABAB heterodimers started this field rapidly followed by the discovery of heteromerization among isoreceptors of several G protein-coupled receptors such as {delta}/{kappa} opioid receptors. Heteromerization was also discovered among distinct types of G protein-coupled receptors with the initial demonstration of somatostatin SSTR5/dopamine D2 and adenosine A1/dopamine D1 heteromeric receptor complexes. The functional meaning of these heteromeric complexes is to achieve direct or indirect (via adapter proteins) intramembrane receptor/receptor interactions in the complex. G protein-coupled receptors also form heteromeric complexes involving direct interactions with ion channel receptors, the best example being the GABAA/dopamine D5 receptor heteromerization, as well as with receptor tyrosine kinases and with receptor activity modulating proteins. As an example, adenosine, dopamine, and glutamate metabotropic receptor/receptor interactions in the striatopallidal GABA neurons are discussed as well as their relevance for Parkinson's disease, schizophrenia, and drug dependence. The heterodimer is only one type of heteromeric complex, and the evidence is equally compatible with the existence of higher order heteromeric complexes, where also adapter proteins such as homer proteins and scaffolding proteins can exist. These complexes may assist in the process of linking G protein-coupled receptors and ion channel receptors together in a receptor mosaic that may have special integrative value and may constitute the molecular basis for some forms of learning and memory.

Address correspondence to: Kjell Fuxe, Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden. E-mail: Kjell.Fuxe{at}neuro.ki.se




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