How and why do GPCRs dimerize?

doi:10.1016/j.tips.2008.02.004

Trends in Pharmacological Sciences

Volume 29, Issue 5, May 2008, Pages 234-240

https://doi.org/10.1016/j.tips.2008.02.004 Get rights and content

Dimerization is fairly common in the G-protein-coupled receptor (GPCR) superfamily. First attempts to rationalize this phenomenon gave rise to an idea that two receptors in a dimer could be necessary to bind a single molecule of G protein or arrestin. Although GPCRs, G proteins and arrestins were crystallized only in their inactive conformations (in which they do not interact), the structures appeared temptingly compatible with this beautiful model. However, it did not survive the rigors of experimental testing: several recent studies unambiguously demonstrated that one receptor molecule is sufficient to activate a G protein and bind arrestin. Thus, to figure out the biological role of receptor self-association we must focus on other functions of GPCRs at different stages of their functional cycle.

Section snippets

GPCR dimerization: the phenomenon and underlying mechanisms

Some GPCRs dimerize, but the functional role of receptor self-association in most cases is unclear. Despite dozens of publications on the subject, as far as the most numerous rhodopsin-like receptors are concerned, unambiguous evidence is sparse [24]. In contrast, there is no doubt that class C receptors exist and function as stable dimers. The molecular mechanisms of their dimerization and signaling were studied extensively, providing valuable clues applicable to other GPCRs.

In addition to the

Receptor coupling to G proteins

How many active HDs are necessary to activate a G protein? This question actually was asked in physiological studies testing the limits of two sensory systems: vertebrate vision [29] and invertebrate olfaction [30]. These experiments, performed in the 1970s when nobody even suspected that in both cases the response is mediated by structurally related receptors, gave identical answers: just one. Sensory cells of Bombyx mori, male silkworm moths, respond to a single molecule of female pheromone

Do GPCR dimers have special functions?

The requirement of a single HD for G-protein coupling does not mean that active receptors never self-associate. Dimerization could serve as a desensitization mechanism, rapidly suppressing G-protein-mediated signaling when there are too many active receptors around. The nanomolar self-association constant of the neurotensin NTS1 receptor and the significant reduction of its signaling efficiency upon dimerization [25], as well as more efficient coupling of monomeric rhodopsin to transducin [38],

Conclusions

Many GPCRs form oligomers of varying stability, from permanent covalently linked dimers to kiss-and-run encounters. Recent rigorous studies showed that a single GPCR (or a single heptahelical domain of a naturally dimeric receptor) is necessary and sufficient to bind a G protein or arrestin, ruling out the hypothesis that two receptors in a dimer are required for these interactions. Therefore, to elucidate the biological significance of receptor dimerization, we need to focus on other GPCR

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Trends in Pharmacological Sciences

OpinionHow and why do GPCRs dimerize?

Section snippets

GPCR dimerization: the phenomenon and underlying mechanisms

Receptor coupling to G proteins

Do GPCR dimers have special functions?

Conclusions

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Curr. Opin. Struct. Biol.

Neuron

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Neuron

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta.

Trends Neurosci.

J. Mol. Biol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

Structure

J. Mol. Biol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Structure

Pharmacol. Ther.

Vision Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Mol. Biol.

G protein-coupled time travel: evolutionary aspects of GPCR research

Mol. Interv.

Mechanism of activation and inactivation of opsin: role of Glu113 and Lys296

Biochemistry

Opinion
How and why do GPCRs dimerize?