Mediation by 5‐hydroxytryptamine<sub>2B</sub> receptors of endothelium‐dependent relaxation in rat jugular vein

Ellis, E.S.; Byrne, Clare R.; Murphy, Olive E.; Tilford, Nicholas S.; Baxter, G.S.

doi:10.1111/j.1476-5381.1995.tb13240.x

Cited by 92 publications

(60 citation statements)

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“…Mastomys carcinoid tumor primary cultures, clonal neural-like 1C11* /5HT serotonergic cells and 5-HT 2B receptor transfected LM6 fibroblasts, the 5-HT 2 receptor agonist DOI (or 5-HT, data not shown) always triggers intracellular cGMP accumulation resulting from both cNOS and iNOS activation. Such a link between 5-HT and NO could already be suspected in view of the simultaneous involvement of these two agents in smooth muscle contractility (6,30), vascular contraction (7,31), and related migraine pathogenesis (32). Because 5-HT 2B receptors are present in stomach, intestine, pulmonary smooth muscles, kidney, as well as in myocardium, vascular endothelium, and meningeal tissues (3,33,34), they are obvious candidates to trigger the NO response associated to 5-HT.…”

Section: Discussionmentioning

confidence: 99%

“…In both cases, the receptor couples with PIP 2 hydrolysis, similarly to the two other members (5-HT 2A and 5-HT 2C ) of the 5-HT 2 receptor family. In contrast, the 5-HT 2B receptor stimulation fails to stimulate PIP 2 hydrolysis in rat fundus (6) and in rat vasculature (7). Signaling processes involving 5-HT 2B receptors and distinct from PIP 2 hydrolysis might thus occur.…”

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confidence: 98%

“…The possibility that NO, a major messenger molecule in the cardiovascular, immune, and nervous systems (see Ref. 9 for review), may behave as a signaling effector associated to the 5-HT 2B receptor, is suggested by data obtained in rat vasculature (7), rat fundus (6), and human endothelial cells (10).…”

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PDZ-dependent Activation of Nitric-oxide Synthases by the Serotonin 2B Receptor

Manivet

Mouillet-Richard

Crinon

et al. 2000

Journal of Biological Chemistry

115

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Taking advantage of three cellular systems, we established that 5-HT 2B receptors are coupled with NO signaling pathways. In the 1C11 serotonergic cell line and Mastomys natalensis carcinoid cells, which naturally express the 5-HT 2B receptor, as well as in transfected LMTK ؊ fibroblasts, stimulation of the 5-HT 2B receptor triggers intracellular cGMP production through dual activation of constitutive nitric-oxide synthase (cNOS) and inducible NOS (iNOS). The group I PDZ motif at the C terminus of the 5-HT 2B receptor is required for recruitment of the cNOS and iNOS transduction pathways. Indeed, the 5-HT 2B receptor-mediated NO coupling is abolished not only upon introduction of a competitor C-terminal 5-HT 2B peptide in the three cell types but also in LMTK ؊ fibroblasts expressing a receptor C-terminally truncated or harboring a point mutation within the PDZ domain. The occurrence of a direct functional coupling between the receptor and cNOS activity is supported by highly significant correlations between the binding constants of drugs on the receptor and their effects on cNOS activity. The 5-HT 2B /iNOS coupling mechanisms appear more complex because neutralization of endogenous G␣ 13 by specific antibodies cancels the cellular iNOS response while not interfering with cNOS activities. These findings may shed light on physiological links between the 5-HT 2B receptor and NO and constitute the first demonstration that PDZ interactions participate in downstream transductional pathways of a G protein-coupled receptor.The monoamine serotonin (5-hydroxytryptamine; 5-HT) 1 modulates a wide variety of human behavioral and physiological processes, such as sleep, anxiety, and cognition, as well as memory, perception, cardiovascular function, smooth muscle response, and gastrointestinal contraction (1, 2). So far, the diversity of 5-HT receptors and the lack of specific pharmacological tools have impaired the investigation of the precise roles of these proteins in the signaling networks that mediate 5-HT physiological functions. This is particularly true in the case of the 5-HT 2B receptor, which, like all the 15 known mammalian 5-HT receptor subtypes but one (5-HT 3 ), belongs to the G protein-coupled receptors (GPCRs). 5-HT 2B receptors cDNA were cloned from the rat stomach fundus, mouse brain, human liver, and neuroblastoma cell lines (see Ref. 3 for review). The 5-HT 2B receptor could be expressed either by transfection or endogeneously during the serotonergic neuronal differentiation of 1C11 cells, referred to as 1C11* /5HT cells (4, 5). In both cases, the receptor couples with PIP 2 hydrolysis, similarly to the two other members (5-HT 2A and 5-HT 2C ) of the 5-HT 2 receptor family. In contrast, the 5-HT 2B receptor stimulation fails to stimulate PIP 2 hydrolysis in rat fundus (6) and in rat vasculature (7). Signaling processes involving 5-HT 2B receptors and distinct from PIP 2 hydrolysis might thus occur. Accordingly, 5-HT 2B -dependent activations of both the ras-mitogen-activated protein kinase cascade (8) and ...

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Section: Discussionmentioning

confidence: 99%

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confidence: 98%

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PDZ-dependent Activation of Nitric-oxide Synthases by the Serotonin 2B Receptor

Manivet

Mouillet-Richard

Crinon

et al. 2000

Journal of Biological Chemistry

115

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“…It has previously been suggested that endothelial 5-HT2c receptors mediate 5-HT-induced relaxation in porcine pulmonary artery (Glusa & Richter, 1993) and rat jugular vein (Bodelsson et al, 1993), but ketanserin (1 gM) failed to cause antagonism, which is inconsistent with its submicromolar affinity for 5-HT2c receptors and leaves open the possibility of mediation through 5-HT2B receptors. Ellis et al (1995) have indeed recently suggested that endothelium-dependent relaxation of rat jugular vein by 5-HT is mediated through 5-HT2B…”

Section: Effects Of Skandf 103829mentioning

confidence: 97%

Participation of 5‐HT₁‐like and 5‐HT_2A receptors in the contraction of human temporal artery by 5‐hydroxytryptamine and related drugs

Verheggen

Freudenthaler

Meyer-Dulheuer

et al. 1996

British J Pharmacology

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1 We investigated the hypothesis that, as in some other large human arteries, 5-HT-induced contraction of the temporal artery is mediated through two co-existing receptor populations, 5-HT,-like-and 5-HT2A. Temporal arterial segments were obtained from patients undergoing brain surgery and rings prepared set up to contract with 5-HT and related agents. 2 In rings with intact endothelium 5-HT evoked contractions with a -log EC50, M of 7.0. Ketanserin (10-1000 nM) antagonized part of the 5-HT-induced contractions. Ketanserin-resistant components of 5-HT-induced contractions were found with -log EC50, M of 6.9 and f1 of 0.17 (100 nM ketanserin) andlog ECso M of 6.4 and f, of 0.20 (1000 nM ketanserin).3 In rings with endothelial function attenuated by enzymatic treatment, 5-HT caused contractions with a -log EC50, M of 7.2 that were partially blocked by ketanserin. Ketanserin-resistant components of 5-HT-induced contractions were found with -log EC50, M 7.4 and f1 of 0.16 (100 nM ketanserin) and -log EC50, M of 7.5 and fi of 0.14 (1000 nM ketanserin). 4 The ketanserin-resistant component of 5-HT-evoked contraction was blocked by methiothepin (100-1000 nM) consistent with mediation through 5-HT,-like receptors. 5 In rings with intact endothelium the 5-HT1-like-selective agonist, sumatriptan, caused small contractions with a -log EC50, M of 6.5 and intrinsic activity of 0.21 with respect to 5-HT that were resistant to blockade by 1000 nM ketanserin but antagonized by 100 nM methiothepin. 6 In rings with intact endothelium the 5-HT2A receptor partial agonist SK&F 103829 (2,3,4,5-tetrahydro-8[methyl sulphonyl]-1H3-benzazepin-7-ol methensulphonate) contracted rings with a -log EC50, M of 5.0 and an intrinsic activity of 0.49 with respect to 5-HT; the effects were antagonized by ketanserin 1000 nM. 7 We conclude that 80-86% of the maximum 5-HT-evoked contraction of human temporal artery is

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“…In other vascular beds, 5-HT can induce endothelium-dependent vasodilation via the 5-HT 2C receptor (Bodelson et al, 1993), the 5-HT 2B receptor (Glusa & Roos, 1996;Ellis et al, 1995) and the 5-HT 1D/1B receptor (Gupta, 1992). There is also evidence that 5-HT can mediate vasodilation directly through 5-HT 4 and 5-HT 7 receptors located on vascular smooth muscle (Cocks & Arnold, 1992;Leung et al, 1996;Terron, 1996).…”

Section: Introductionmentioning

confidence: 99%

5‐Hydroxytryptamine receptors mediating vasoconstriction and vasodilation in perinatal and adult rabbit small pulmonary arteries

Morecroft

MacLean

1998

British J Pharmacology

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1 Vasoconstrictor responses to 5-HT, 5-carboxamidotryptamine (5-CT, 5-HT 1 receptor agonist), amethyl-5-HT (5-HT 2 receptor agonist) and sumatriptan (5-HT 1D/1B receptor agonist) were studied in fetal, 0 ± 24 h, 4 day, 7 day and adult rabbit pulmonary resistance arteries (PRAs), alone and in the presence of the NO synthase inhibitor N o -nitro-L-arginine methylester (L-NAME). The e ect of the selective 5-HT receptor antagonists ketanserin (5-HT 2A receptor) and GR55562 (5-HT 1B/1D receptor) on vasoconstrictor responses to 5-HT were studied in the presence of L-NAME. Vasodilator responses to 5-CT were also studied in pre-contracted PRAs. 3 5-HT and a-methyl-5-HT were equipotent in causing contraction in the PRAs at each age (e.g. pEC 50 s for 5-HT and a-methyl-5-HT were 6.74+0.13 and 6.63+0.22 respectively in adult vessels). In the perinatal PRAs, sumatriptan and 5-CT produced negligible contractions, but in adult PRAs, 5-CT and sumatriptan were potent agonists with pEC 50 s of 6.05+0.3 and 5.70+0.20 respectively. 4 L-NAME markedly increased the maximum response to 5-HT in the 0 ± 24 h, 4 day and 7 day vessels and increased 5-HT potency in the 4-, 7-day-old and adult rabbit vessels. 5 In perinatal vessels, responses to 5-HT, with L-NAME present, were antagonized by ketanserin (30 nM and 0.1 mM) but not GR55562 (1 mM). A small ketanserin-resistant, GR55562-sensitive component was observed at 0 ± 24 h. In adult vessels, both ketanserin and GR55562 inhibited 5-HTinduced responses. 7 Vasodilator responses to 5-CT were observed in pre-contracted PRAs from 4-and 7-day-old rabbits but not in the fetus, 0 ± 24 h old or adult rabbit vessels. At 4 days the vasodilator response was inhibited both by L-NAME and GR55562. At 7 days the response was only partly blocked by L-NAME and resistant to GR55562. The L-NAME resistant component was antagonized by the 5-HT 7 receptor antagonist spiperone (1 mM). 8 The results suggest that 5-HT 2A -receptors mediate vasoconstriction in perinatal vessels whilst the 5-HT 1D or 5-HT 1B receptor contributes in adult rabbit vessels. The 5-HT 1D or 5-HT 1B receptor mediates NO-dependent vasodilation in vessels from rabbits at 4 days of age whilst 5-HT 7 receptors mediate NOindependent vasodilation by 7 days.

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Mediation by 5‐hydroxytryptamine_2B receptors of endothelium‐dependent relaxation in rat jugular vein

Abstract: 1 An 'atypical' 5-HT2 receptor which is located on the endothelium of rat jugular vein has been described. In the present study we 4 These data are consistent with the presence of 5-HT2B receptors mediating endothelium-dependent relaxation of rat jugular vein.

Cited by 92 publications

References 12 publications

PDZ-dependent Activation of Nitric-oxide Synthases by the Serotonin 2B Receptor

PDZ-dependent Activation of Nitric-oxide Synthases by the Serotonin 2B Receptor

Participation of 5‐HT₁‐like and 5‐HT_2A receptors in the contraction of human temporal artery by 5‐hydroxytryptamine and related drugs

5‐Hydroxytryptamine receptors mediating vasoconstriction and vasodilation in perinatal and adult rabbit small pulmonary arteries

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Mediation by 5‐hydroxytryptamine2B receptors of endothelium‐dependent relaxation in rat jugular vein

Abstract: 1 An 'atypical' 5-HT2 receptor which is located on the endothelium of rat jugular vein has been described. In the present study we 4 These data are consistent with the presence of 5-HT2B receptors mediating endothelium-dependent relaxation of rat jugular vein.

Cited by 92 publications

References 12 publications

PDZ-dependent Activation of Nitric-oxide Synthases by the Serotonin 2B Receptor

PDZ-dependent Activation of Nitric-oxide Synthases by the Serotonin 2B Receptor

Participation of 5‐HT1‐like and 5‐HT2A receptors in the contraction of human temporal artery by 5‐hydroxytryptamine and related drugs

5‐Hydroxytryptamine receptors mediating vasoconstriction and vasodilation in perinatal and adult rabbit small pulmonary arteries

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Mediation by 5‐hydroxytryptamine_2B receptors of endothelium‐dependent relaxation in rat jugular vein

Participation of 5‐HT₁‐like and 5‐HT_2A receptors in the contraction of human temporal artery by 5‐hydroxytryptamine and related drugs