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Trends Pharmacol Sci. 2015 Mar;36(3):145-52. doi: 10.1016/ Epub 2015 Feb 18.

The GPCR heterotetramer: challenging classical pharmacology.

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Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health (NIH), Triad Technology Building, 333 Cassell Drive, Baltimore, MD 21224, USA. Electronic address:


Two concepts are gaining increasing acceptance in G protein-coupled receptor (GPCR) pharmacology: (i) pre-coupling of GPCRs with their preferred signaling molecules, and (ii) GPCR oligomerization. This is begging for the introduction of new models such as GPCR oligomer-containing signaling complexes with GPCR homodimers as functional building blocks. This model favors the formation of GPCR heterotetramers - heteromers of homodimers coupled to their cognate G protein. The GPCR heterotetramer offers an optimal framework for a canonical antagonistic interaction between activated Gs and Gi proteins, which can simultaneously bind to their respective preferred receptors and to adenylyl cyclase (AC) catalytic units. This review addresses the current evidence for pre-coupling of the various specific components that provide the very elaborate signaling machinery exemplified by the Gs-Gi-AC-coupled GPCR heterotetramer.


GPCR; adenylyl cyclase; oligomerization; signalosome

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