Trends in Endocrinology & Metabolism
ReviewLessons from constitutively active mutants of G protein-coupled receptors
Section snippets
Lessons from CAMs on the molecular mechanisms of GPCR activation
Activation of a GPCR requires a change in its conformation that triggers G protein activation, but also induces other protein interactions involved in signal transduction and receptor traffic. CAMs are thought to mimic to some extent the active conformation of the wt receptor and to adopt spontaneously a structure able to activate G proteins. The position and nature of the mutations thus provide clues to the differences between the inactive and the active conformations (Fig. 2).
The most
Lessons from CAMs on the regulation and traffic of GPCRs
There is increasing evidence that GPCRs, after agonist binding, not only activate G protein(s) but are also able to interact with a large variety of proteins, which in turn activate other signaling pathways or the desensitization of the receptor. Desensitization usually involves phosphorylation by specific and non-specific kinases and arrestin binding, which prevents interaction with G proteins and recruits the internalization and recycling machineries [37]. After internalization, the receptor
Lessons from CAMs on the role of GPCRs in pathology
The discovery that a hormone receptor can present unregulated and ligand-independent activity was rapidly correlated with autonomous hormonal secretion in several endocrine diseases. The role of CAMs in human disease was first demonstrated in 1993 for the thyrotropin (TSH) receptor in hyperfunctioning thyroid adenoma [49]. Several dozen mutations affecting the TM or extracellular domains of this GPCR activate constitutively (i.e. in absence of TSH ligand) the cAMP signaling pathway (Fig. 2).
Conclusion
CAMs have provided a useful tool to study the activation mechanisms and the pathophysiology of GPCRs, in spite of their structural differences with the agonist-linked active state(s). From these studies emerge some new concepts which might lead to very speculative hypotheses on GPCR physiology, illustrated by two examples. (1) Similar to the characterization of receptor subtypes, identification of multiple conformational active states of a given GPCR suggests the existence of different
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