Elsevier

Pharmacology & Therapeutics

Volume 111, Issue 3, September 2006, Pages 949-973
Pharmacology & Therapeutics

Inactivating mutations of G protein-coupled receptors and diseases: Structure-function insights and therapeutic implications

https://doi.org/10.1016/j.pharmthera.2006.02.008Get rights and content

Abstract

Since the discovery of the first rhodopsin mutation that causes retinitis pigmentosa in 1990, significant progresses have been made in elucidating the pathophysiology of diseases caused by inactivating mutations of G protein-coupled receptors (GPCRs). This review aims to compile the compelling evidence accumulated during the past 15 years demonstrating the etiologies of more than a dozen diseases caused by inactivating GPCR mutations. A generalized classification scheme, based on the life cycle of GPCRs, is proposed. Insights gained through detailed studies of these naturally occurring mutations into the structure-function relationship of these receptors are reviewed. Therapeutic approaches directed against the different classes of mutants are being developed. Since intracellular retention emerges as the most common defect, recent progresses aimed at correcting this defect through membrane permeable pharmacological chaperones are highlighted.

Introduction

G protein-coupled receptors (GPCRs) comprise the largest family of cell surface proteins, with more than 1000 members in humans. They transduce a large variety of extracellular signals, including light, smell, ions, catecholamines, neuropeptides, and large glycoprotein hormones (Bockaert & Pin, 1999). GPCRs consist of seven transmembrane Ī±-helices (TMs) connected by alternating extracellular and intracellular loops (ELs and ILs), with the N terminus extracellular and the C terminus intracellular. The crystal structure of rhodopsin at high resolution confirmed this topology (Palczewski et al., 2000). Almost all known physiological processes are regulated by GPCRs. Therefore it is easy to understand that defects in these signaling pathways will lead to various dysfunctions and diseases. Since the discovery of the first naturally occurring mutation in GPCRs causing human disease (Dryja et al., 1990), the list for diseases caused by GPCR mutations keeps expanding (for an exhaustive list see (Schoneberg et al., 2004)). A number of excellent reviews on diseased GPCRs have been published (Spiegel et al., 1993, Shenker, 1995, Spiegel, 1996, Schoneberg et al., 2002, Spiegel & Weinstein, 2004).

The purpose of this review is to summarize the studies in 15 GPCRs where multiple pathogenic loss-of-function mutations have been reported. Only overt mutations are covered. Polymorphic variants are not discussed herein. Interested readers are referred to recent reviews (Rana et al., 2001, Sadee et al., 2001). Based on the life cycle of the GPCRs, a general classification scheme is suggested for categorizing the ever-increasing mutations in these GPCRs. Insights that can be learned from the functional studies of the naturally occurring mutations in these GPCRs as well as the therapeutic implications are also highlighted.

Section snippets

Rhodopsin mutations and retinitis pigmentosa

Rhodopsin, the dim-light receptor, is one of the best-studied model systems in GPCRs. After absorption of light (photons), rhodopsin undergoes conformational changes and is converted to metarhodopsin II, the active form of rhodopsin. Metarhodopsin II activates the heterotrimeric G protein in rod cells, transducin, initiating the photo-transduction cascade.

The first mutation in GPCRs that cause human diseases was found in rhodopisn, P23H, causing autosomal dominant retinitis pigmentosa (ADRP) (

Towards a molecular classification of inactivating GPCR mutations

GPCRs begin their life with the transcription of their mRNAs in the nucleus and the synthesis of the polypeptides on the ribosome. These polypeptides are inserted into the ER membrane co-translationaly. Most of the GPCRs are glycoproteins. Therefore carbohydrates are added onto the polypeptides in the ER, specifically carbohydrates of the immature type containing high mannose. After initial folding, with the assistance of molecular chaperones such as calnexin and calreticulin, the receptors are

Insights into the structure-function of GPCRs

Careful characterizations of naturally occurring mutations of GPCRs that cause diseases not only provide novel insights into the physiological and pathophysiological roles of the underlying systems, but also shed lights on the structure-function relationships of the GPCRs. Experiments of nature provided us a lot of excellent clues. Below we summarize some of the lessons learned in these respects.

Class I mutants: Aminoglycosides

Although missense mutations are the most common loss-of-function mutations, a significant portion, which varies among the receptors, are nonsense and frameshift mutations that truncate the receptors prematurely. Previous studies in other genetic diseases caused by nonsense mutations discovered that aminoglycoside antibiotics, by binding to the decoding site on the ribosome, could decrease the codon-antocodon proofreading efficiency resulting in read-through of the premature stop codon. Using

Conclusions

During the past 15Ā years, an ever-expanding list of diseases caused by inactivating mutations in GPCRs has appeared in scientific literature. With a few exceptions (such as rhodopin, V2R, MC3R, and MC4R), the mode of inheritance is autosomal recessive for these diseases. Patients are either homozygous or compound heterozygous. We reviewed the literature where multiple mutations in 15 GPCRs have been identified to cause diseases. In vitro functional studies of these naturally occurring mutations

Acknowledgments

I sincerely apologize to those scientists whose outstanding contributions to this field could not be cited due to space limitations. Numerous investigators identified and functionally characterized rhodopsin and V2 receptor mutations that amounts to more than 100 each. It is not possible to cite all the relevant papers. I thank Dr. Deborah L. Segaloff for introducing me into the field of diseased GPCRs. My studies on the neural melanocortin receptors and human obesity, supported by American

References (326)

  • V. Chhajlani et al.

    Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA

    FEBS Lett

    (1992)
  • H. Choe et al.

    The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates

    Cell

    (1996)
  • A.J. Clark et al.

    Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor

    Lancet

    (1993)
  • A.J. Clark et al.

    Inherited ACTH insensitivity illuminates the mechanisms of ACTH action

    Trends Endocrinol Metab

    (2005)
  • B.J. Doranz et al.

    A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors

    Cell

    (1996)
  • B. Dubern et al.

    Mutational analysis of melanocortin-4 receptor, agouti-related protein, and Ī±-melanocyte-stimulating hormone genes in severely obese children

    J Pediatr

    (2001)
  • M.T. Duvernay et al.

    The regulatory mechanisms of export trafficking of G protein-coupled receptors

    Cell Signal

    (2005)
  • P.A. Frandberg et al.

    Human pigmentation phenotype: a point mutation generates nonfunctional MSH receptor

    Biochem Biophys Res Commun

    (1998)
  • R.R. Franke et al.

    Structure and function in rhodopsin. Studies of the interaction between the rhodopsin cytoplasmic domain and transducin

    J Biol Chem

    (1992)
  • I. Gantz et al.

    Molecular cloning of a novel melanocortin receptor

    J Biol Chem

    (1993)
  • J. Gromoll et al.

    Functional and clinical consequences of mutations in the FSH receptor

    Mol Cell Endocrinol

    (1996)
  • M.J. Abramowicz et al.

    Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland

    J Clin Invest

    (1997)
  • K. Aida et al.

    Familial hypocalciuric hypercalcemia associated with mutation in the human Ca2+-sensing receptor gene

    J Clin Endocrinol Metab

    (1995)
  • K. Aittomaki et al.

    Clinical features of primary ovarian failure caused by a point mutation in the follicle stimulating hormone receptor gene

    J Clin Endocrinol Metab

    (1996)
  • Y. Ala et al.

    Functional studies of twelve mutant V2 vasopressin receptors related to nephrogenic diabetes insipidus: molecular basis of a mild clinical phenotype

    J Am Soc Nephrol

    (1998)
  • M. Alba et al.

    Naturally-occurring missense mutations in the human growth hormone-releasing hormone receptor alter ligand binding

    J Endocrinol

    (2005)
  • L. Alberti et al.

    Germline mutations of TSH receptor gene as cause of nonautoimmune subclinical hypothyroidism

    J Clin Endocrinol Metab

    (2002)
  • G. Alkhatib et al.

    CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1

    Science

    (1996)
  • L.A. Allen et al.

    A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics

    Hum Reprod

    (2003)
  • J. Amiel et al.

    Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease

    Hum Mol Genet

    (1996)
  • M. Ascoli et al.

    The lutropin/choriogonadotropin receptor, a 2002 perspective

    Endocr Rev

    (2002)
  • T. Attie et al.

    Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease

    Hum Mol Genet

    (1995)
  • A. Auricchio et al.

    Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population

    Hum Mol Genet

    (1996)
  • M. Bai et al.

    In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+-sensing receptor gene: normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia

    J Clin Invest

    (1997)
  • L.S. Barak et al.

    Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus

    Proc Natl Acad Sci U S A

    (2001)
  • E.R. Barton-Davis et al.

    Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice

    J Clin Invest

    (1999)
  • I. Beau et al.

    A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor

    J Clin Invest

    (1998)
  • K.A. Beaumont et al.

    Altered cell surface expression of human MC1R variant receptor alleles associated with red hair and skin cancer risk

    Hum Mol Genet

    (2005)
  • M. Beranova et al.

    Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism

    J Clin Endocrinol Metab

    (2001)
  • V. Bernier et al.

    Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus

    J Am Soc Nephrol

    (2006)
  • H. Biebermann et al.

    Mutations of the human thyrotropin receptor gene causing thyroid hypoplasia and persistent congenital hypothyroidism

    J Clin Endocrinol Metab

    (1997)
  • H. Biebermann et al.

    Autosomal-dominant mode of inheritance of a melanocortin-4 receptor mutation in a patient with severe early-onset obesity is due to a dominant-negative effect caused by receptor dimerization

    Diabetes

    (2003)
  • M. Birnbaumer et al.

    An extracellular congenital nephrogenic diabetes insipidus mutation of the vasopressin receptor reduces cell surface expression, affinity for ligand, and coupling to the Gs/adenylyl cyclase system

    Mol Endocrinol

    (1994)
  • C. Blanpain et al.

    CCR5 and HIV infection

    Receptors Channels

    (2002)
  • J. Bockaert et al.

    Molecular tinkering of G protein-coupled receptors: an evolutionary success

    EMBO J

    (1999)
  • D.W. Bowden et al.

    Linkage of genetic markers on human chromosomes 20 and 12 to NIDDM in Caucasian sib pairs with a history of diabetic nephropathy

    Diabetes

    (1997)
  • N.F. Box et al.

    Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair

    Hum Mol Genet

    (1997)
  • S.P. Brothers et al.

    Unexpected effects of epitope and chimeric tags on gonadotropin-releasing hormone receptors: implications for understanding the molecular etiology of hypogonadotropic hypogonadism

    J Clin Endocrinol Metab

    (2003)
  • C.R. Brown et al.

    Chemical chaperones correct the mutant phenotype of the delta F508 cystic fibrosis transmembrane conductance regulator protein

    Cell Stress Chaperones

    (1996)
  • A.A. Butler et al.

    A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse

    Endocrinology

    (2000)
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