Constitutive Activity of Serotonin2C Receptors at G Protein-Independent Signaling: Modulation by RNA Editing and Antidepressants

Labasque, Marilyne; Meffre, Julie; Carrat, Gaëlle; Bécamel, Carine; Bockaert, Joël; Marin, Philippe

doi:10.1124/mol.110.066035

Cited by 37 publications

(42 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that exposure to FLX during adolescence decreased ERK2, RSK, CREB, and mTOR phosphorylation within the VTA, with no change in total levels of these proteins. These findings are consistent with studies demonstrating that FLX exposure blocks ERK phosphorylation in vivo (Fumagalli et al, 2005;in vitro (Stepulak et al, 2008;Labasque et al, 2010), resulting in decreased ERK activity (Carlini et al, 2012). Our data, therefore, strongly indicate that the behavioral and therapeutic effects of FLX are mediated, at least in part, via decreases in ERK2 activity within the VTA.…”

Section: Discussionsupporting

confidence: 90%

Fluoxetine Exposure during Adolescence Alters Responses to Aversive Stimuli in Adulthood

et al. 2014

View full text Add to dashboard Cite

The mechanisms underlying the enduring neurobiological consequences of antidepressant exposure during adolescence are poorly understood. Here, we assessed the long-term effects of exposure to fluoxetine (FLX), a selective serotonin reuptake inhibitor, during adolescence on behavioral reactivity to emotion-eliciting stimuli. We administered FLX (10 mg/kg, bi-daily, for 15 d) to male adolescent [postnatal day 35 (P35) to P49] C57BL/6 mice. Three weeks after treatment (P70), reactivity to aversive stimuli (i.e., social defeat stress, forced swimming, and elevated plus maze) was assessed. We also examined the effects of FLX on the expression of extracellular signalregulated kinase (ERK) 1/2-related signaling within the ventral tegmental area (VTA) of adolescent mice and Sprague Dawley rats. Adolescent FLX exposure suppressed depression-like behavior, as measured by the social interaction and forced swim tests, while enhancing anxiety-like responses in the elevated plus maze in adulthood. This complex behavioral profile was accompanied by decreases in ERK2 mRNA and protein phosphorylation within the VTA, while stress alone resulted in opposite neurobiological effects. Pharmacological (U0126) inhibition, as well as virus-mediated downregulation of ERK within the VTA mimicked the antidepressant-like profile observed after juvenile FLX treatment. Conversely, overexpression of ERK2 induced a depressive-like response, regardless of FLX pre-exposure. These findings demonstrate that exposure to FLX during adolescence modulates responsiveness to emotion-eliciting stimuli in adulthood, at least partially, via long-lasting adaptations in ERK-related signaling within the VTA. Our results further delineate the role ERK plays in regulating mood-related behaviors across the lifespan.

show abstract

Section: Discussionsupporting

confidence: 90%

Fluoxetine Exposure during Adolescence Alters Responses to Aversive Stimuli in Adulthood

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Furthermore, 247R-induced proliferation is normalized upon treatment with MMP or EGFR inhibitors, as well as β-arrestin1 or MMP7-specific shRNAs. Although recently agonist-independent constitutive activation of serotonin receptor was reported in transiently transfected HEK293 cells (21), the authors did not examine whether this finding led to EFGR transactivation and cell proliferation. Thus, to our knowledge, this report of constitutive β-arrestin1/ MMP7/EGFR transactivation for any GPCR is unique.…”

Section: Discussionmentioning

confidence: 99%

Constitutive coupling of a naturally occurring human alpha1a-adrenergic receptor genetic variant to EGFR transactivation pathway

Oganesian

Yarov‐Yarovoy

Parks³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

We previously identified a naturally occurring human SNP, G247R, in the third intracellular loop of the α 1a -adrenergic receptor (α 1a -247R) and demonstrated that constitutive expression of α 1a -247R results in twofold increased cell proliferation compared with WT. In the present study we elucidate molecular mechanisms and signal transduction pathways responsible for increased cell proliferation unique to α 1a -247R, but not α 1a -WT, α 1b , or α 1d AR subtypes. We show that elevated levels of matrix metalloproteinase-7 (MMP7) and a disintegrin and metalloproteinase-12 (ADAM12) in α 1a -247R-expressing cells are responsible for EGF receptor (EGFR) transactivation, downstream ERK activation, and increased cell proliferation; this pathway is confirmed using MMP, EGFR, and ERK inhibitors. We demonstrate that EGFR transactivation and downstream ERK activation depends on increased shedding of heparin-binding EGF. Finally, we demonstrate that knockdown of MMP7 or β-arrestin1 by shRNAs results in attenuation of proliferation of cells expressing α 1a -247R. Importantly, accelerated cell proliferation triggered by the α 1a -247R is serum-and agonist-independent, providing unique evidence for constitutive active coupling to the β-arrestin1/MMP/EGFR transactivation pathway by any G protein-coupled receptor. These findings raise the possibility of a previously unexplored mechanism for sympathetically mediated human hypertension triggered by a naturally occurring human genetic variant.

show abstract

“…5-HT 2C Rs undergo desensitization by β-arrestin owing to constitutive activation or 5-HT (Marion et al 2004;Labasque et al 2008;Labasque et al 2010), indicating that monitoring 5-HT 2C R activity by the Tango system is feasible. Therefore, we have developed and show utility of a 5-HT 2C R-Tango system visualized using the EGFP reporter gene.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, the Tango assay system has the advantage in sensitivity for weak signals because it transforms GPCRarrestin interaction into a stable and amplifiable reporter gene signal that records receptor activation (Barnea et al 2008). It was previously reported that constitutively active 5-HT 2C R interacts with β-arrestin (Marion et al 2004;Labasque et al 2010). In the present study, we detected 5-HT 2C R-Tango activity even in 5-HT-unstimulated cells, demonstrating the system has sufficient sensitivity to monitor 5-HT 2C R activity.…”

Section: Discussionmentioning

confidence: 99%

Development of the 5-HT2CR-Tango System Combined with an EGFP Reporter Gene

et al. 2015

View full text Add to dashboard Cite

The serotonin 2C receptor (5-HT2CR) is a G-protein-coupled receptor implicated in emotion, feeding, reward, and cognition. 5-HT2CRs are pharmacological targets for mental disorders and metabolic and reward system abnormalities, as alterations in 5-HT2CR expression, RNA editing, and SNPs are involved in these disturbances. To date, 5-HT2CR activity has mainly been measured by quantifying inositol phosphate production and intracellular Ca(2+) release, but these assays are not suitable for in vivo analysis. Here, we developed a 5-HT2CR-Tango assay system, a novel analysis tool of 5-HT2CR activity based on the G-protein-coupled receptor (GPCR)-arrestin interaction. With desensitization of activated 5-HT2CR by arrestin, this system converts the 5-HT2CR-arrestin interaction into EGFP reporter gene signal via the LexA transcriptional activation system. For validation of our system, we measured activity of two 5-HT2CR RNA-editing isoforms (INI and VGV) in HEK293 cells transfected with EGFP reporter gene. The INI isoform displayed both higher basal- and 5-HT-stimulated activities than the VGV isoform. Moreover, an inhibitory effect of 5-HT2CR antagonist SB242084 was also detected by 5-HT2CR-Tango system. This novel tool is useful for in vitro high-throughput targeted 5-HT2CR drug screening and can be applied to future in vivo brain function studies associated with 5-HT2CRs in transgenic animal models.

show abstract

Constitutive Activity of Serotonin2C Receptors at G Protein-Independent Signaling: Modulation by RNA Editing and Antidepressants

Cited by 37 publications

References 41 publications

Fluoxetine Exposure during Adolescence Alters Responses to Aversive Stimuli in Adulthood

Fluoxetine Exposure during Adolescence Alters Responses to Aversive Stimuli in Adulthood

Constitutive coupling of a naturally occurring human alpha1a-adrenergic receptor genetic variant to EGFR transactivation pathway

Development of the 5-HT2CR-Tango System Combined with an EGFP Reporter Gene

Contact Info

Product

Resources

About