Journal ArticleDOI
Constitutive Activity of Serotonin2C Receptors at G Protein-Independent Signaling: Modulation by RNA Editing and Antidepressants
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TLDR
Basal ERK1/2 phosphorylation in 5-HT2C-INI receptor-expressing cells was abolished and evidence of constitutive activity of a G protein-coupled receptor toward G-independent, β-arrestin-dependent, receptor signaling is provided.Abstract:
Serotonin (5-HT)2C receptor is a Gq-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-HT2C 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-HT2C-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-HT2C-VGV) receptors. Basal ERK1/2 phosphorylation in 5-HT2C-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-HT2C 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-HT2C receptors. Reminiscent of agonist-induced ERK1/2 phosphorylation, basal activity in HEK 293 cells was unaffected by cellular depletion of Gαq/11 and Gα13 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-HT2C-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.read more
Citations
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Journal ArticleDOI
New therapeutic opportunities for 5-HT2C receptor ligands in neuropsychiatric disorders.
TL;DR: Evidence of the preclinical efficacy of 5-HT2C ligands in numerous behavioral tests modeling human diseases is reviewed, highlighting the multiple and competing actions of the 5- HT2CRs in neurobiological networks and monoaminergic systems.
Journal ArticleDOI
International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function
Nicholas M. Barnes,Gerard P. Ahern,Carine Bécamel,Joël Bockaert,Michael Camilleri,Severine Chaumont-Dubel,Sylvie Claeysen,Kathryn A. Cunningham,Kevin C. Fone,Michael Gershon,Giuseppe Di Giovanni,Nathalie M. Goodfellow,Adam L. Halberstadt,Rachel M. Hartley,Ghérici Hassaine,Katharine Herrick-Davis,Ruud Hovius,Enza Lacivita,Evelyn K. Lambe,Marcello Leopoldo,Finn Olav Levy,Sarah C. R. Lummis,Philippe Marin,Luc Maroteaux,Andrew C. McCreary,David Nelson,John F. Neumaier,Adrian Newman-Tancredi,Hugues Nury,Alexander Roberts,Bryan L. Roth,Anne Roumier,Gareth J. Sanger,Milt Teitler,Trevor Sharp,Carlos M. Villalón,Horst Vogel,Stephanie W. Watts,Daniel Hoyer,Daniel Hoyer +39 more
TL;DR: In this article, a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit, is provided, where appropriate, the utility of therapeutics targeting these receptors.
Journal ArticleDOI
Serotonergic signaling: multiple effectors and pleiotropic effects
Justine Masson,Justine Masson,M. B. Emerit,M. B. Emerit,Michel Hamon,Michel Hamon,Michèle Darmon,Michèle Darmon +7 more
TL;DR: The emerging signaling model includes the capacity of 5-HT receptors GPCR superfamily to couple and initiate transduction through several G proteins depending on the tissue and/or the presence of interacting proteins.
Journal ArticleDOI
Transcript diversification in the nervous system: a to I RNA editing in CNS function and disease development.
Aamira Tariq,Michael F. Jantsch +1 more
TL;DR: The mechanisms of RNA editing are described and target mRNAs of editing that are functionally relevant to normal and aberrant CNS activity are focused on.
Journal ArticleDOI
Serotonin-2C and -2a receptor co-expression on cells in the rat medial prefrontal cortex
Christine Nocjar,Christine Nocjar,Katherine D Alex,Katherine D Alex,Alex Sonneborn,Atheir I. Abbas,Bryan L. Roth,Elizabeth A. Pehek,Elizabeth A. Pehek +8 more
TL;DR: A complex interplay of cortical 5-HT2A and 5- HT2C receptor mechanisms exists, which if altered, could modulate efferent brain systems implicated in mental illness.
References
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Journal ArticleDOI
Regulation of serotonin-2C receptor G-protein coupling by RNA editing
Colleen M. Burns,Hsin Chu,Susan M. Rueter,Linda K. Hutchinson,Hervé Canton,Elaine Sanders-Bush,Ronald B. Emeson +6 more
TL;DR: Observations indicate that RNA editing is a new mechanism for regulating serotonergic signal transduction and suggest that this post-transcriptional modification may be critical for modulating the different cellular functions that are mediated by other members of the G-protein-coupled receptor superfamily.
Journal ArticleDOI
β-Arrestin-dependent, G Protein-independent ERK1/2 Activation by the β2 Adrenergic Receptor
Sudha K. Shenoy,Matthew T. Drake,Christopher D. Nelson,Daniel A. Houtz,Kunhong Xiao,Srinivasan Madabushi,Eric Reiter,Eric Reiter,Richard T. Premont,Olivier Lichtarge,Robert J. Lefkowitz +10 more
TL;DR: It is demonstrated that the β2AR can signal to ERK via a GRK5/6-β-arrestin-dependent pathway, which is independent of G protein coupling, and GRK2, membrane translocation of which requires Gβγ release upon G protein activation, was ineffective unless it was constitutively targeted to the plasma membrane by a prenylation signal.
Journal ArticleDOI
Antidepressants increase neural progenitor cells in the human hippocampus
Maura Boldrini,Maura Boldrini,Mark D. Underwood,René Hen,Gorazd Rosoklija,Gorazd Rosoklija,Andrew J. Dwork,J. John Mann,Victoria Arango +8 more
TL;DR: The increase of NPCs and dividing cells in MDDT was localized to the rostral DG, and whether this finding is critical or necessary for the antidepressants effect remains to be determined.
Journal ArticleDOI
Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application.
TL;DR: A diversity of multi-target strategies are proposed for the more efficacious and rapid control of core and co-morbid symptoms of depression, together with improved tolerance relative to currently available agents.
Journal ArticleDOI
Distinct β-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation
Diane Gesty-Palmer,Minyong Chen,Eric Reiter,Seungkirl Ahn,Christopher D. Nelson,Shuntai Wang,Allen E. Eckhardt,Conrad L. Cowan,Robert F. Spurney,Louis M. Luttrell,Louis M. Luttrell,Robert J. Lefkowitz +11 more
TL;DR: It is concluded that PTH stimulates ERK1/2 through several distinct signal transduction pathways: an early G protein-dependent pathway meditated by PKA and PKC and a late pathway independent of G proteins mediated through β-arrestins.