Defects in G protein-coupled signal transduction in human disease

Research output: Contribution to journalArticle

179 Citations (Scopus)

Abstract

G proteins couple receptors for many hormones and neurotransmitters to effectors that regulate second messenger metabolism. G protein-coupled receptors comprise a superfamily with the common structural feature of a single polypeptide with seven membrane-spanning domains. G proteins themselves are heterotrimers with an α subunit that binds guanine nucleotides. In the basal state, G proteins tightly bind GDP; receptor activation allows exchange of bound GDP for GTP that activates the G protein and causes it to modulate effector activity. An intrinsic GTPase activity hydrolyzes bound GTP to GDP thereby deactivating the G protein. The effects (cholera, whooping cough) of bacterial toxins that target G proteins for covalent modification signal the potential importance of G protein dysfunction as a cause of human disease. Conceptually, G protein dysfunction could involve gain or loss of function. For G(s), examples of both types have already been defined. Mutations in G protein-coupled receptors have also been identified in several human diseases. Germline loss of function mutations in rhodopsin, cone opsins, the V2 vasopressin receptor, ACTH receptor, and calcium-sensing receptor are responsible for retinitis pigmentosa, color blindness, nephrogenic diabetes insipidus, familial ACTH resistance, and familial hypocalciuric hypercalcemia, respectively. Missense mutations that cause constitutive receptor activation have been identified in the TSH and LH receptors.

Original languageEnglish (US)
Pages (from-to)143-170
Number of pages28
JournalAnnual Review of Physiology
Volume58
StatePublished - 1996
Externally publishedYes

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GTP-Binding Proteins
Signal Transduction
G-Protein-Coupled Receptors
Guanosine Triphosphate
Cone Opsins
Corticotropin Receptors
Nephrogenic Diabetes Insipidus
Color Vision Defects
Bacterial Toxins
Calcium-Sensing Receptors
LH Receptors
Thyrotropin Receptors
Vasopressin Receptors
Mutation
Retinitis Pigmentosa
Rhodopsin
Guanine Nucleotides
Whooping Cough
Cholera
GTP Phosphohydrolases

Keywords

  • endocrine hyperfunction
  • GTPase
  • hormone resistance
  • mutations
  • receptor

ASJC Scopus subject areas

  • Physiology

Cite this

Defects in G protein-coupled signal transduction in human disease. / Spiegel, Allen M.

In: Annual Review of Physiology, Vol. 58, 1996, p. 143-170.

Research output: Contribution to journalArticle

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