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  • Review Article
  • Published:

G protein-coupled receptors: mutations and endocrine diseases

Abstract

Over the past 20 years, naturally occurring mutations that affect G protein-coupled receptors (GPCRs) have been identified, mainly in patients with endocrine diseases. The study of loss-of-function or gain-of-function mutations has contributed to our understanding of the pathophysiology of several diseases with classic hypophenotypes or hyperphenotypes of the target endocrine organs, respectively. Simultaneously, study of the mutant receptors ex vivo was instrumental in delineating the relationships between the structure and function of these important physiological and pharmacological molecules. Now that access to the crystallographic structure of a few GPCRs is available, the mechanics of these receptors can be studied at the atomic level. Progress in the fields of cell biology, molecular pharmacology and proteomics has also widened our view of GPCR functions. Initially considered simply as guanine nucleotide exchange factors capable of activating G protein-dependent regulatory cascades, GPCRs are now known to display several additional characteristics, each susceptible to alterations by disease-causing mutations. These characteristics include functionally important basal activity of the receptor; differential activation of various G proteins; differential activation of G protein-dependent and independent effects (biased agonism); interaction with proteins that modify receptor function; dimerization-dependent effects; and interaction with allosteric modulators. This Review attempts to illustrate how natural mutations of GPCR could contribute to our understanding of these novel facets of GPCR biology.

Key Points

  • G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors

  • GPCRs are key factors in endocrinology, as they are the main sensors of the internal environment

  • Hereditary and congenital forms of classic endocrine diseases that display hypophenotyes or hyperphenotypes of the target endocrine organs are attributable to loss-of-function or gain-of-function mutations of GPCRs, respectively

  • In addition to their canonical role as guanine nucleotide exchange factors, GPCRs have a series of G protein-independent effects that might be the cause of many endocrine diseases

  • Endocrine phenotypes resulting from mutations that affect noncanonical functions of GPCRs remain to be identified

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Figure 1: Binding of its agonist to a GPCR causes a conformational change that activates the guanine nucleotide exchange function of the receptor towards one of the possible interacting heterotrimeric Gαβγ proteins.
Figure 2: GPCR loss-of-function mutations.
Figure 3: Gain-of-function mutations of GPCRs.
Figure 4: Gain-of-function mutations that affect GPCR specificity: the example of the glycoprotein hormone receptors.

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Vassart, G., Costagliola, S. G protein-coupled receptors: mutations and endocrine diseases. Nat Rev Endocrinol 7, 362–372 (2011). https://doi.org/10.1038/nrendo.2011.20

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