Review
doi: 10.1186/1756-6606-4-20.GPCR oligomers in pharmacology and signaling
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- PMID:21619615
- PMCID: PMC3128055
- DOI: 10.1186/1756-6606-4-20
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Review
GPCR oligomers in pharmacology and signaling
Javier González-Maeso. Mol Brain..
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Abstract
G protein-coupled receptors (GPCRs) represent one of the largest families of cell surface receptors, and are the target of more than half of the current therapeutic drugs on the market. When activated by an agonist, the GPCR undergoes conformational changes that facilitate its interaction with heterotrimeric G proteins, which then relay signals to downstream intracellular effectors. Although GPCRs were thought to function as monomers, many studies support the hypothesis that G protein coupling involves the formation of GPCR homo- and/or hetero-complexes. These complex systems have been suggested to exhibit specific signaling cascades, pharmacological, internalization, and recycling properties. In this review, we summarize recent advances in our understanding of the structure, function and dynamics of GPCR complexes, as well as the findings obtained in animal models.
Figures
G protein-dependent signaling and behavioral responses that require a GPCR heterocomplex. Hallucinogenic drugs, such as lysergic acid diethylamide (LSD), mescaline and psilocybin, all have in common a high affinity for the serotonin 5-HT2Areceptor. Metabotropic glutamate 2 receptor (mGlu2) and serotonin 5-HT2Areceptor form a specific functional GPCR heterocomplex in mammalian brain and in tissue culture preparations. mGlu2transmembrane domains 4/5 mediate association with the 5-HT2Areceptor. When 5-HT2Aand mGlu2are prevented from forming a receptor heterocomplex, activation of 5-HT2Aby LSD elicits signaling characteristic of Gq/11-protein subtypes. In contrast, LSD acting at the 5-HT2A-mGlu2receptor heterocomplex activates both Gq/11- and Gi/o-dependent signaling. Head-twitch behavior is reliably and robustly elicited by hallucinogenic 5-HT2Aagonists, and is absent in mGlu2knockout mice.
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