期刊
MOLECULAR BIOLOGY OF THE CELL
卷 19, 期 11, 页码 4640-4650出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E08-04-0422
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资金
- Centre National de la Recherche Scientifique
- Institut National de la Sante et de la Recherche Medicale, the French Minister of Research [ACI-JC 5075]
- Fondation pour la Recherche Medicale
The serotonin (5- hydroxytryptamine; 5- HT)(2C) receptor is a G protein-coupled receptor ( GPCR) exclusively expressed in CNS that has been implicated in numerous brain disorders, including anxio-depressive states. Like many GPCRs, 5-HT2C receptors physically interact with a variety of intracellular proteins in addition to G proteins. Here, we show that calmodulin (CaM) binds to a prototypic Ca2+-dependent 1-10 CaM-binding motif located in the proximal region of the 5-HT2C receptor C-terminus upon receptor activation by 5-HT. Mutation of this motif inhibited both beta-arrestin recruitment by 5-HT2C receptor and receptor-operated extracellular signal-regulated kinase (ERK) 1,2 signaling in human embryonic kidney-293 cells, which was independent of G proteins and dependent on beta-arrestins. A similar inhibition was observed in cells expressing a dominant-negative CaM or depleted of CaM by RNA interference. Expression of the CaM mutant also prevented receptor-mediated ERK1,2 phosphorylation in cultured cortical neurons and choroid plexus epithelial cells that endogenously express 5-HT2C receptors. Collectively, these findings demonstrate that physical interaction of CaM with recombinant and native 5-HT2C receptors is critical for G protein-independent, arrestin-dependent receptor signaling. This signaling pathway might be involved in neurogenesis induced by chronic treatment with 5-HT2C receptor agonists and their antidepressant-like activity.
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