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Mol Pharmacol. 2010 Nov;78(5):818-26. doi: 10.1124/mol.110.066035. Epub 2010 Aug 10.

Constitutive activity of serotonin 2C receptors at G protein-independent signaling: modulation by RNA editing and antidepressants.

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Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5203, Institut de Génomique Fonctionnelle, Université Montpellier 1 and 2, Montpellier, France.


Serotonin (5-HT)(2C) receptor is a G(q)-coupled receptor exhibiting a high degree of constitutive activity toward phospholipase C effector pathway, a process regulated by receptor mRNA editing. In addition to G protein-dependent signaling, 5-HT(2C) receptors also activate the extracellular signal-regulated kinase (ERK) 1/2 pathway independently of receptor coupling to G proteins. Constitutive activity at ERK signaling has not yet been explored. Transient expression of unedited 5-HT(2C-INI) receptors in human embryonic kidney (HEK) 293 cells resulted in a marked increase in ERK1/2 phosphorylation compared with nontransfected cells. No increase in ERK1/2 phosphorylation was measured in cells expressing fully edited (5-HT(2C-VGV)) receptors. Basal ERK1/2 phosphorylation in 5-HT(2C-INI) receptor-expressing cells was abolished by 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole (SB206,553), a 5-HT(2C) inverse agonist toward phospholipase C. This effect was prevented by the neutral antagonist 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl]indoline (SB242,084), which alone did not alter basal activity. Similar observations were made in vivo in mouse choroid plexus, a structure rich in constitutively active 5-HT(2C) receptors. Reminiscent of agonist-induced ERK1/2 phosphorylation, basal activity in HEK 293 cells was unaffected by cellular depletion of Gα(q/11) and Gα(13) proteins but strongly reduced in cells expressing a dominant-negative β-arrestin or depleted of β-arrestin by RNA interference and in cells expressing a dominant-negative calmodulin or a 5-HT(2C-INI) receptor mutant not capable of interacting with calmodulin. The tetracyclic antidepressants mirtazapine and mianserin likewise reduced basal ERK activation. On the other hand, the m-chlorophenylpiperazine derivative trazodone and the selective serotonin reuptake inhibitor fluoxetine were inactive alone but blocked 5-HT-induced ERK1/2 phosphorylation. Together, these data provide the first evidence of constitutive activity of a G protein-coupled receptor toward G-independent, β-arrestin-dependent, receptor signaling.

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