G protein-coupled receptor structure and function: The impact of disease-causing mutations

https://doi.org/10.1016/S0950-351X(95)80519-2Get rights and content

Summary

Just as the discovery of ‘inborn errors of metabolism’ in humans contributed to our basic understanding of normal enzymatic pathways, so can genetic defects in signal transduction help to elucidate the functions normally subserved by different GPCR pathways. Identification and characterization of naturally occurring GPCR mutations not only has inherent value in understanding the molecular basis of disease, but can also accelerate progress in understanding the fundamental mechanisms involved in GPCR synthesis, transport to the membrane, ligand binding, activation and deactivation.

References (114)

  • FindlayJ et al.

    Three-dimensional modelling of G protein-linked receptors

    Trends in Pharmacological Sciences

    (1990)
  • FitzpatrickVD et al.

    Agonist selectivity determinants in somatostatin receptor subtypes I and II

    Journal of Biological Chemistry

    (1994)
  • HedinKE et al.

    Specificity of receptor-G protein interactions: searching for the structure behind the signal

    Cellular Signalling

    (1993)
  • HendersonR et al.

    Model for the structure of bacteriorhodopsin based on high-resolution electron cryo-microscopy

    Journal of Molecular Biology

    (1990)
  • HeplerJR et al.

    G proteins

    Trends in Biochemical Sciences

    (1992)
  • HibertMF et al.

    This is not a G protein-coupled receptor

    Trends in Pharmacological Sciences

    (1993)
  • HollandFJ

    Gonadotropin-independent precocious puberty

    Endocrinology and Metabolism Clinics of North America

    (1991)
  • JiI et al.

    Asp383 in the second transmembrane domain of the lutropin receptor is important for high affinity hormone binding and cAMP production

    Journal of Biological Chemistry

    (1991)
  • JiI et al.

    Receptor activation of and signal generation by the lutropin/choriogonadotropin receptor

    Cooperation of Asp397 of the receptor and αLys91 of the hormone

    Journal of Biological Chemistry

    (1993)
  • KjelsbergMA et al.

    Constitutive activation of the α1B-adrenergic receptor by all amino acid substitutions at a single site: evidence for a region which constrains receptor activation

    Journal of Biological Chemistry

    (1992)
  • KosugiS et al.

    The third exoplasmic loop of the thyrotropin receptor is partially involved in signal transduction

    FEBS Letters

    (1994)
  • KosugiS et al.

    Mutation of alanine 623 in the third cytoplasmic loop of the rat thyrotropin (TSH) receptor results in a loss in the phosphoinositide but not cAMP signal induced by TSH and receptor antibodies

    Journal of Biological Chemistry

    (1992)
  • KosugiS et al.

    Constitutive activation of cyclic AMP but not phosphatidylinositol signaling caused by four mutations in the 6th transmembrane helix of the human thyrotropin receptor

    FEBS Letters

    (1994)
  • LeongSR et al.

    Complete mutagenesis of the extracellular domain of interleukin-8 (IL-8) type A receptor identifies charged residues mediating IL-8 binding and signal transduction

    Journal of Biological Chemistry

    (1994)
  • NankoS et al.

    Dopamine D4 receptor polymorphism and schizophrenia

    Lancet

    (1993)
  • NathansJ

    In the eye of the beholder: visual pigments and inherited variation in human vision

    Cell

    (1994)
  • OliveiraL et al.

    A common step for signal transduction in G protein-coupled receptors

    Trends in Pharmacological Sciences

    (1994)
  • PerlmanJH et al.

    A model of the thyrotropin-releasing hormone (TRH) receptor binding pocket

    Evidence for a second direct interaction between transmembrane helix 3 and TRH

    Journal of Biological Chemistry

    (1994)
  • PrivesC

    How loops, β sheets, and α helices help us to understand p 53

    Cell

    (1994)
  • RenQ et al.

    Constitutively active mutants of the α2-adrenergic receptor

    Journal of Biological Chemistry

    (1993)
  • RobbinsLS et al.

    Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function

    Cell

    (1993)
  • RobinsonPR et al.

    Constitutively active mutants of rhodopsin

    Neuron

    (1992)
  • SamamaP et al.

    A mutation-induced activated state of the β2-adrenergic receptor: extending the ternary complex model

    Journal of Biological Chemistry

    (1993)
  • SchwartzTW

    Locating ligand-binding sites in 7TM receptors by protein engineering

    Current Opinion in Biotechnology

    (1994)
  • ShaikhS et al.

    Dopamine D4 receptor subtypes and response to clozapine

    Lancet

    (1993)
  • AdachiM et al.

    Identification of a ligand-binding site of the human endothelin-A receptor and specific regions required for ligand selectivity

    European Journal of Biochemistry

    (1994)
  • AllenLF et al.

    G-protein-coupled receptor genes as protooncogenes: constitutively activating mutation of the α1B-adrenergic receptor enhances mitogenesis and tumorigenicity

  • ArnisS et al.

    Two different forms of metarhodopsin II: Schiff base deprotonation precedes proton uptake and signaling state

  • BaldwinJM

    The probable arrangement of the helices in G protein-coupled receptors

    EMBO Journal

    (1993)
  • BirnbaumerM

    Mutations and diseases of G protein coupled receptors

    Journal of Receptor and Signal Transduction Research

    (1995)
  • BlümlK et al.

    Insertion mutagenesis as a tool to predict the secondary structure of a muscarinic receptor domain determining specificity of G-protein coupling

  • BoeppleP et al.

    Activating mutations of the LH receptor in sporadic male gonadotropin-independent precocious puberty

  • BooneC et al.

    Mutations that alter the third cytoplasmic loop of the a-factor receptor lead to a constitutive and hypersensitive phenotype

  • CacalanoG et al.

    Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor homolog

    Science

    (1994)
  • de la ChapelleA et al.

    Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis

  • CohenGB et al.

    Mechanism of activation and inactivation of opsin: role of Glu113 and Lys296

    Biochemistry

    (1992)
  • CohenGB et al.

    Constitutive activation of opsin: influence of charge at position 134 and size at position 296

    Biochemistry

    (1993)
  • ConklinBR et al.

    Marriage of the flytrap and the serpent

    Nature

    (1994)
  • CuddihyRM et al.

    A genomic TSH receptor point mutation is highly associated with autoimmune thyroid disease in females

    Thyroid

    (1994)
  • DavidsonFF et al.

    Structure and function in rhodopsin: replacement by alanine of cysteine residues 110 and 187, components of a conserved disulfide bond in rhodopsin, affects the light-activated metarhodopsin II state

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