Constitutive dimerization of human serotonin 5‐HT<sub>4</sub> receptors in living cells

Berthouze, Magali; Ayoub, Mohammed Akli; Russo, Olivier; Rivail, Lucie; Sicsic, Sames; Fischmeister, Rodolphe; Berque‐Bestel, Isabelle; Jockers, Ralf; Lezoualc’h, Frank

doi:10.1016/j.febslet.2005.04.040

Cited by 63 publications

(59 citation statements)

References 34 publications

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“…It is conceivable that these unidentified isoforms may be less efficiently activated by metoclopramide than the variants that were detected in pheochromocytomas explants. In addition, recent studies have shown that 5-HT 4 receptors, like other G-proteincoupled receptors, can form homo-and/or heterodimers that modulate receptor function (Berthouze et al 2005). It is thus possible that differences in the expression profiles of 5-HT 4 receptor splice variants among tissues could lead to a weak responsiveness to metoclopramide in normal adrenal medulla in comparison with pheochromocytomas.…”

Section: Discussionmentioning

confidence: 99%

Metoclopramide stimulates catecholamine- and granin-derived peptide secretion from pheochromocytoma cells through activation of serotonin type 4 (5-HT4) receptors

Guillemot¹,

Compagnon²,

Cartier³

et al. 2009

Endocrine-Related Cancer

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The gastroprokinetic agent metoclopramide is known to stimulate catecholamine secretion from pheochromocytomas. The aim of the study was to investigate the mechanism of action of metoclopramide and expression of serotonin type 4 (5-HT 4 ) receptors in pheochromocytoma tissues. Tissue explants, obtained from 18 pheochromocytomas including the tumor removed from a 46-year-old female patient who experienced life-threatening hypertension crisis after metoclopramide administration and 17 additional pheochromocytomas (9 benign and 8 malignant) were studied. Cultured pheochromocytoma cells derived from the patient who previously received metoclopramide were incubated with metoclopramide and various 5-HT 4 receptor ligands. In addition, total mRNAs were extracted from all the 18 tumors. Catecholamine-and granin-derived peptide concentrations were measured in pheochromocytoma cell incubation medium by HPLC and radioimmunological assays. In addition, expression of 5-HT 4 receptor mRNAs in the 18 pheochromocytomas was investigated by the use of reverse transcriptase-PCR. Results: Metoclopramide and the 5-HT 4 receptor agonist cisapride were found to activate catecholamineand granin-derived peptide secretions by cultured tumor cells. Metoclopramide-and cisaprideevoked catecholamine-and granin-derived peptide productions were inhibited by the 5-HT 4 receptor antagonist GR 113808. 5-HT 4 receptor mRNAs were detected in the patient's tumor and the series of 17 additional pheochromocytomas. This study shows that pheochromocytomas express functional 5-HT 4 receptors that are responsible for the stimulatory action of metoclopramide on catecholamine-and granin-derived peptide secretion. All 5-HT 4 receptor agonists must therefore be contraindicated in patients with proven or suspected pheochromocytoma.

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Section: Discussionmentioning

confidence: 99%

Metoclopramide stimulates catecholamine- and granin-derived peptide secretion from pheochromocytoma cells through activation of serotonin type 4 (5-HT4) receptors

Guillemot¹,

Compagnon²,

Cartier³

et al. 2009

Endocrine-Related Cancer

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“…Furthermore, some GPCRs have been tested for their ability to heterodimerize with melatonin receptors. No heterodimers were observed with the b2-adrenoreceptor, the serotonin 5-HT4 receptor and the chemokine receptor CCR5 (Ayoub et al, 2002(Ayoub et al, , 2004Berthouze et al, 2005). Finally, we have to be aware that melatonin may affect infiltration of inflammatory cells by influencing leukocyte rolling and adhesion in microcirculation (Reiter et al, 2000;Cuzzocrea et al, 2000;Lotufo et al, 2001).…”

mentioning

confidence: 85%

A role for melatonin in maintaining the pro- and anti-inflammatory balance by influencing leukocyte migration and apoptosis in carp

Kepka

Szwejser

Pijanowski

et al. 2015

Developmental & Comparative Immunology

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“…Dimerization of 5-HT 4 R at the Cell Surface-Previous studies reported that 5-HT 4 Rs form constitutive dimers in living cells (42). We used TR-FRET tools (32) to confirm that WT 5-HT 4 R monomers could form homodimers and also heterodimers with mutant 5-HT 4 Rs at the cell surface.…”

Section: ) (41)mentioning

confidence: 99%

G Protein Activation by Serotonin Type 4 Receptor Dimers

Pellissier

Barthet

Gaven

et al. 2011

Journal of Biological Chemistry

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The discovery that class C G protein-coupled receptors (GPCRs) function as obligatory dimeric entities has generated major interest in GPCR oligomerization. Oligomerization now appears to be a common feature among all GPCR classes. However, the functional significance of this process remains unclear because, in vitro, some monomeric GPCRs, such as rhodopsin and ␤ 2 -adrenergic receptors, activate G proteins. By using wild type and mutant serotonin type 4 receptors (5-HT 4 Rs) (including a 5-HT 4 -RASSL) expressed in COS-7 cells as models of class A GPCRs, we show that activation of one protomer in a dimer was sufficient to stimulate G proteins. However, coupling efficiency was 2 times higher when both protomers were activated. Expression of combinations of 5-HT 4 , in which both protomers were able to bind to agonists but only one could couple to G proteins, suggested that upon agonist occupancy, protomers did not independently couple to G proteins but rather that only one G protein was activated. Coupling of a single heterotrimeric G s protein to a receptor dimer was further confirmed in vitro, using the purified recombinant WT RASSL 5-HT 4 R obligatory heterodimer. These results, together with previous findings, demonstrate that, differently from class C GPCR dimers, class A GPCR dimers have pleiotropic activation mechanisms. G protein-coupled receptors (GPCRs)2 are key players in cell-cell communication. They transduce a wide range of extracellular signals, such as light, odors, hormones, or neurotransmitters into appropriated cellular responses (1, 2). Signal transduction occurs via conformational changes of the ligandactivated GPCRs, leading to activation of G proteins and their downstream signaling pathways (3).GPCRs have been considered for a long time as monomeric proteins, and the paradigm of "one ligand/one receptor/one G protein" was the driving principle (1). However, a growing number of studies revealed dimerization/oligomerization of GPCRs (4 -8) mostly in heterologous cells (homo-or heterodimers) but also in native tissues or in vivo (dimers) (9 -13). In line with these observations, a recent report described crystal structures of the chemokine receptor CXCR4 that are consistent with the formation of homodimers (14).A relatively accepted model proposes that only one protomer in a dimer is fully activated, even when both binding sites are occupied (15)(16)(17)(18)(19). The activated protomer interacts with the G␣ subunit to accelerate GDP/GTP exchange. This is compatible with recent data showing that a rhodopsin monomer (or a ␤ 2 -adrenergic receptor monomer) is sufficient to activate its cognate G protein after purification and reconstitution in a phospholipid bilayer (20, 21). However, some observations indicate that the active state of a GPCR dimer is asymmetric (22, 23) and that conformational switches occur between protomers (24, 25). Moreover, occupation of the second protomer of a dimer is probably not "silent" because it can either favor (26) or reduce (22) coupling efficiency. It has also ...

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Constitutive dimerization of human serotonin 5‐HT₄ receptors in living cells

Cited by 63 publications

References 34 publications

Metoclopramide stimulates catecholamine- and granin-derived peptide secretion from pheochromocytoma cells through activation of serotonin type 4 (5-HT4) receptors

Metoclopramide stimulates catecholamine- and granin-derived peptide secretion from pheochromocytoma cells through activation of serotonin type 4 (5-HT4) receptors

A role for melatonin in maintaining the pro- and anti-inflammatory balance by influencing leukocyte migration and apoptosis in carp

G Protein Activation by Serotonin Type 4 Receptor Dimers

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Constitutive dimerization of human serotonin 5‐HT4 receptors in living cells

Cited by 63 publications

References 34 publications

Metoclopramide stimulates catecholamine- and granin-derived peptide secretion from pheochromocytoma cells through activation of serotonin type 4 (5-HT4) receptors

Metoclopramide stimulates catecholamine- and granin-derived peptide secretion from pheochromocytoma cells through activation of serotonin type 4 (5-HT4) receptors

A role for melatonin in maintaining the pro- and anti-inflammatory balance by influencing leukocyte migration and apoptosis in carp

G Protein Activation by Serotonin Type 4 Receptor Dimers

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Constitutive dimerization of human serotonin 5‐HT₄ receptors in living cells