G‐protein‐mediated Signal Transduction and Human Disorders


Heterotrimeric G proteins couple to seven‐transmembrane receptors, producing diverse signals to effectors that generate intracellular signals. Loss‐ and gain‐of‐function mutations in genes encoding G‐protein‐coupled receptors and the α subunit of heterotrimeric G proteins have been increasingly recognized as causes of human disease.

Keywords: signal transduction; receptors; G proteins; hormone resistance; second messengers

Figure 1.

The G‐protein GTPase cycle. Potential sites for disease‐causing abnormalities are numbered. Under physiological conditions, effector regulation by G‐protein subunits is transient and is terminated by the GTPase activity of the α subunit. The latter converts bound GTP to GDP, thus returning the α subunit to its inactivated state with high affinity for the βγ dimer, which reassociates again to form the heterotrimer. In the figure, the G protein shown is Gs with its effector, adenylyl cyclase. Activation of adenylyl cyclase generates the intracellular second messenger, cAMP, which activates protein kinase A (PKA). The latter enzyme phosphorylates a variety of proteins that mediate the physiological effects of agonists for Gs‐coupled receptors. Cholera toxin covalently modifies the Gs‐α subunit (αs) blocking its GTPase activity. Somatic mutations of the Gs‐α subunit likewise block GTPase activity. In both cases, constitutive activation and agonist‐independent cAMP formation result. In each case the top of the plasma membrane represents the outside of the cell and the bottom the inside.



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Web Links

Chemokine (C‐C motif) receptor 5 (CCR5); Locus ID: 1234. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1234

Guanine nucleotide binding protein (G protein), beta polypeptide 3 (GNB3); Locus ID: 2784. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2784

Chemokine (C‐C motif) receptor 5 (CCR5); MIM number: 601373. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?601373

Guanine nucleotide binding protein (G protein), beta polypeptide 3 (GNB3); MIM number: 139130. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?139130

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Spiegel, Allen M(Jan 2006) G‐protein‐mediated Signal Transduction and Human Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0005505]