5-Hydroxytryptamine 4(a) Receptor Is Coupled to the Gα Subunit of Heterotrimeric G13 Protein

Ponimaskin, Evgeni; Profirovic, Jasmina; Vaiškunaite, Rita; Richter, Diethelm W.; Voyno-Yasenetskaya, Tatyana A.

doi:10.1074/jbc.m112216200

Cited by 83 publications

(132 citation statements)

References 50 publications

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“…This suggests that a G-protein other than G␣ q might be responsible for at least the majority of the observed constitutive activation of SRE. G 12/13 has previously been suggested to mediate the coupling of several other 7TM receptors to SRE activation through Rho kinase (32). The specific Rho kinase blocker Y-27632 decreased the basal SRE activity in GPR39-transfected cells by ϳ50%, indicating that G 12/13 is involved in the GPR39-induced, ligand-independent stimulation of SRE activation.…”

Section: Figmentioning

confidence: 94%

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Common Structural Basis for Constitutive Activity of the Ghrelin Receptor Family

Holst

Holliday

Bach

et al. 2004

Journal of Biological Chemistry

311

305

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Three members of the ghrelin receptor family were characterized in parallel: the ghrelin receptor, the neurotensin receptor 2 and the orphan receptor GPR39. In transiently transfected COS-7 and human embryonic kidney 293 cells, all three receptors displayed a high degree of ligand-independent signaling activity. The structurally homologous motilin receptor served as a constitutively silent control; upon agonist stimulation, however, it signaled with a similar efficacy to the three related receptors. The constitutive activity of the ghrelin receptor and of neurotensin receptor 2 through the G q , phospholipase C pathway was ϳ50% of their maximal capacity as determined through inositol phosphate accumulation. These two receptors also showed very high constitutive activity in activation of cAMP response element-driven transcription. GPR39 displayed a clear but lower degree of constitutive activity through the inositol phosphate and cAMP response element pathways. In contrast, GPR39 signaled with the highest constitutive activity in respect of activation of serum response element-dependent transcription, in part, possibly, through G 12/13 and Rho kinase. Antibody feeding experiments demonstrated that the epitope-tagged ghrelin receptor was constitutively internalized but could be trapped at the cell surface by an inverse agonist, whereas GPR39 remained at the cell surface. Mutational analysis showed that the constitutive activity of both the ghrelin receptor and GPR39 could systematically be tuned up and down depending on the size and hydrophobicity of the side chain in position VI:16 in the context of an aromatic residue at VII:09 and a large hydrophobic residue at VII:06. It is concluded that the three ghrelin-like receptors display an unusually high degree of constitutive activity, the structural basis for which is determined by an aromatic cluster on the inner face of the extracellular ends of TMs VI and VII.

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Section: Figmentioning

confidence: 94%

“…Signaling through the SRE Pathway-Transcriptional regulation through the SRE pathway has been proposed to be stimulated by various G protein systems, including G␣ 13 , G␣ I , and G␤␥ (32)(33)(34)(35).…”

Section: Resultsmentioning

confidence: 99%

Common Structural Basis for Constitutive Activity of the Ghrelin Receptor Family

Holst

Holliday

Bach

et al. 2004

Journal of Biological Chemistry

311

305

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“…We recently demonstrated coupling between the 5-HT 4 receptor and G13-protein (Ponimaskin et al, 2002). We also have shown that 5-HT 4 receptor-dependent activation of G␣13 leads to RhoA-mediated cell rounding and neurite retraction.…”

Section: Introductionmentioning

confidence: 96%

“…Construction of the 5-HT 4 -pTracer-CMV2 plasmid has been described previously (Ponimaskin et al, 2002). To create 5-HT 7 -green fluorescent protein (GFP) and 5-HT 4 -GFP chimeras with C-terminal GFP fusion, receptor-coding sequences were amplified by PCR and then ligated into the pEGFP-N1 plasmid (Clontech, Cambridge, UK).…”

Section: Methodsmentioning

confidence: 99%

5-HT₇Receptor Is Coupled to Gα Subunits of Heterotrimeric G12-Protein to Regulate Gene Transcription and Neuronal Morphology

Kvachnina¹,

Liu²,

Dityatev³

et al. 2005

J. Neurosci.

180

220

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The neurotransmitter serotonin (5-HT) plays an important role in the regulation of multiple events in the CNS. We demonstrated recently a coupling between the 5-HT 4 receptor and the heterotrimeric G13-protein resulting in RhoA-dependent neurite retraction and cell rounding (Ponimaskin et al., 2002). In the present study, we identified G12 as an additional G-protein that can be activated by another member of serotonin receptors, the 5-HT 7 receptor. Expression of 5-HT 7 receptor induced constitutive and agonist-dependent activation of a serum response element-mediated gene transcription through G12-mediated activation of small GTPases. In NIH3T3 cells, activation of the 5-HT 7 receptor induced filopodia formation via a Cdc42-mediated pathway correlating with RhoA-dependent cell rounding. In mouse hippocampal neurons, activation of the endogenous 5-HT 7 receptors significantly increased neurite length, whereas stimulation of 5-HT 4 receptors led to a decrease in the length and number of neurites. These data demonstrate distinct roles for 5-HT 7 R/G12 and 5-HT 4 R/G13 signaling pathways in neurite outgrowth and retraction, suggesting that serotonin plays a prominent role in regulating the neuronal cytoarchitecture in addition to its classical role as neurotransmitter.

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“…5-HT 4 Rs are coupled to the G s /cAMP/protein kinase A pathway (9). Other signal transduction pathways have also been reported, but mainly in heterologous transfected cells (2,10,11).…”

Section: -Hydroxytryptamine 4 Receptors (5-htmentioning

confidence: 99%

Uncoupling and Endocytosis of 5-Hydroxytryptamine 4 Receptors

Barthet

Gaven

Framery

et al. 2005

Journal of Biological Chemistry

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The 5-hydroxytryptamine type 4 receptors (5-HT 4 Rs) are involved in memory, cognition, feeding, respiratory control, and gastrointestinal motility through activation of a G s /cAMP pathway. We have shown that 5-HT 4 R undergoes rapid and profound homologous uncoupling in neurons. However, no significant uncoupling was observed in COS-7 or HEK293 cells, which expressed either no or a weak concentration of GRK2, respectively. High expression of GRK2 in neurons is likely to be the reason for this difference because overexpression of GRK2 in COS-7 and HEK293 cells reproduced rapid and profound uncoupling of 5-HT 4 R. We have also shown, for the first time, that GRK2 requirements for uncoupling and endocytosis were very different. Indeed, ␤-arrestin/dynamindependent endocytosis was observed in HEK293 cells without any need of GRK2 overexpression. In addition to this difference, uncoupling and ␤-arrestin/dynamindependent endocytosis were mediated through distinct mechanisms. Neither uncoupling nor ␤-arrestin/dynamin-dependent endocytosis required the serine and threonine residues localized within the specific C-terminal domains of the 5-HT 4 R splice variants. In contrast, a cluster of serines and threonines, common to all variants, was an absolute requirement for ␤-arrestin/ dynamin-dependent receptor endocytosis, but not for receptor uncoupling. Furthermore, ␤-arrestin/dynamindependent endocytosis and uncoupling were dependent on and independent of GRK2 kinase activity, respectively. These results clearly demonstrate that the uncoupling and endocytosis of 5-HT 4 R require different GRK2 concentrations and involve distinct molecular events.

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5-Hydroxytryptamine 4(a) Receptor Is Coupled to the Gα Subunit of Heterotrimeric G13 Protein

Cited by 83 publications

References 50 publications

Common Structural Basis for Constitutive Activity of the Ghrelin Receptor Family

Common Structural Basis for Constitutive Activity of the Ghrelin Receptor Family

5-HT₇Receptor Is Coupled to Gα Subunits of Heterotrimeric G12-Protein to Regulate Gene Transcription and Neuronal Morphology

Uncoupling and Endocytosis of 5-Hydroxytryptamine 4 Receptors

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5-Hydroxytryptamine 4(a) Receptor Is Coupled to the Gα Subunit of Heterotrimeric G13 Protein

Cited by 83 publications

References 50 publications

Common Structural Basis for Constitutive Activity of the Ghrelin Receptor Family

Common Structural Basis for Constitutive Activity of the Ghrelin Receptor Family

5-HT7Receptor Is Coupled to Gα Subunits of Heterotrimeric G12-Protein to Regulate Gene Transcription and Neuronal Morphology

Uncoupling and Endocytosis of 5-Hydroxytryptamine 4 Receptors

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5-HT₇Receptor Is Coupled to Gα Subunits of Heterotrimeric G12-Protein to Regulate Gene Transcription and Neuronal Morphology