Protease-activated receptors mediate apamin-sensitive relaxation of mouse and guinea pig gastrointestinal smooth muscle

Cocks, T. M.; Sozzi, Vitina; Moffatt, James D.; Selemidis, Stavros

doi:10.1016/s0016-5085(99)70180-0

Cited by 99 publications

(123 citation statements)

References 31 publications

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“…Although the mechanical effects induced by PAR-1 and PAR-2 activation are reported to be TTX-insensitive Corvera et al, 1997;Cocks et al, 1999b;Kawabata et al, 1999;Mule`et al, 2002a), recent studies have indicated that PAR-1 and PAR-2 can be present in the enteric neurones in guinea-pig and porcine small intestine (Corvera et al, 1999;Green et al, 2000). The previously reported lack of effect of TTX (Mule`et al, 2002a) supports the hypothesis that both inhibitory and contractile responses to PAR-1 and PAR-2 are independent by propagation of neural action potential, but it does not exclude that prejunctional PARs may directly induce release of mediators.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study in vivo has provided evidence for an increase of the mouse gastrointestinal transit in response to PAR-1 and PAR-2 activation (Kawabata et al, 2001). There is also in vitro evidence that PARs modulate smooth muscle mechanical activity and their activation can induce relaxant, contractile or biphasic responses (Al-Ani et al, 1995;Saifeddine et al, 1996;Corvera et al, 1997;Hollenberg et al, 1997;Kawabata et al, 1999;Cocks et al, 1999b;Mule`et al, 2002a).…”

Section: Introductionmentioning

confidence: 99%

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Involvement of nitric oxide and tachykinins in the effects induced by protease‐activated receptors in rat colon longitudinal muscle

Mulè

Baffi

Capparelli

et al. 2003

British J Pharmacology

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1 The aim of the present study was to verify a possible involvement of nitric oxide (NO) and of tachykinins in the contractile and relaxant effects caused by the activation of protease-activated receptor (PAR)-1 and PAR-2 in the longitudinal muscle of rat colon. 2 Mechanical responses to the PAR-1 activating peptides, SFLLRN-NH 2 (10 nM -10 mM) and TFLLR-NH 2 (10 nM -10 mM), and to the PAR-2-activating peptide, SLIGRL-NH 2 (10 nM -10 mM), were examined in vitro in the absence and in the presence of different antagonists. The contractile responses to PAR-1 and PAR-2 activation were concentration-dependently attenuated by SR140333 (0.1 -1 mM), NK 1 receptor antagonist, or by SR48968 (0.1 -1 mM), NK 2 receptor antagonist. The combined pretreatment with SR140333 (1 mM) and SR48968 (1 mM) produced additive suppressive effects on the contractile responses to PAR activation. Pretreatment of the preparation with capsaicin (10 mM) markedly reduced the contractions evoked by SFLLRN-NH 2 , TFLLR-NH 2 and SLIGRL-NH 2 , while o-conotoxin GVIA (0.2 mM) had no effect. 5 The present results suggest that in rat colonic longitudinal muscle, PAR-1 and PAR-2 activation can evoke (i) relaxation through the production of NO or (ii) contraction through the release of tachykinins, likely, from sensory nerves. These actions may contribute to motility disturbances during intestinal trauma and inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Involvement of nitric oxide and tachykinins in the effects induced by protease‐activated receptors in rat colon longitudinal muscle

Mulè

Baffi

Capparelli

et al. 2003

British J Pharmacology

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“…P roteinase-activated receptors (PARs) 3 are a novel family of G-protein coupled receptors that are activated by the proteolytic unmasking of a tethered ligand at their N terminus. Four members of this family have been cloned and identified; among them PAR-1, -3, and -4 are cleaved by thrombin, whereas PAR-2 is activated by trypsin and mast cell tryptase (1,2).…”

mentioning

confidence: 99%

“…These peptides have been used as selective agonists for studying the function of PARs in vivo and in vitro. Although PARs were first discovered in a search for the receptors mediating the hormone-like effects of thrombin on platelets, subsequent studies showed their widespread expression in different cell types in the gastrointestinal, cardiovascular, respiratory, genitourinary, and central, and peripheral nervous systems (3)(4)(5)(6)(7)(8)(9). All four PARs have been shown to be expressed in the CNS, while their activating proteases can either be produced within the brain or originate from extravasated plasma during inflammatory processes (10).…”

mentioning

confidence: 99%

Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

Noorbakhsh

Vergnolle

McArthur

et al. 2005

The Journal of Immunology

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Proteinase-activated receptors (PARs), a newly discovered subgroup of G-protein coupled receptors, are widely expressed by neural cells, but their roles in the nervous system remain uncertain. In this study, we report that PAR-2 was up-regulated on neurons in conjunction with neuroinflammation in brain tissue from patients with HIV-1-associated dementia. The inflammatory cytokines TNF-α and IL-1β were also increased in HIV-1-associated dementia brains compared with patients without dementia (p < 0.05), but these same cytokines induced PAR-2 expression on neurons. Enhanced PAR-2 expression and subsequent activation prevented neuronal cell death and induction of the tumor suppressor, p53, caused by the HIV-encoded protein, Tat (p < 0.01). Intrastriatal implantation of a PAR-2 peptide agonist also inhibited Tat-induced neurotoxicity in a mouse model of HIV neuropathogenesis (p < 0.05). Moreover, PAR-2 null animals showed more severe neuroinflammation and neuronal loss caused by Tat neurotoxicity (p < 0.05). TNF-α protected wild-type neurons from Tat-related neurotoxicity, but in PAR-2-deficient neurons, the same concentrations of TNF-α were cytotoxic (p < 0.001). Thus, neuroinflammation can exert protective effects by which it induces PAR-2 expression with the ensuing abrogation of neuronal death.

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“…PAR2 (F2RL1) is one of the four known PARs and has been shown to play a role in secretion, smooth muscle contractility, neuromodulation, inflammation, fibrosis, angiogenesis and cancer metastasis (Bertog et al, 1999;Cocks et al, 1999;Danahay et al, 2001;Fiorucci et al, 2001;Hoogerwerf et al, 2001;Richard et al, 2001;Vergnolle et al, 2001;Frungieri et al, 2002;Hollenberg, 2002;Milia et al, 2002). We found that increased PAR2 expression enhanced, and reduced expression decreased, growth of RCC cell lines in vitro, suggesting that upregulation of TMSNB and PAR2 following VHL inactivation contributes to RCC tumorigenesis, although, we note that TMSNB and PAR2 were only upregulated in a proportion of primary RCC with VHL inactivation.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel VHL targets that are associated with the development of renal cell carcinoma

et al. 2006

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von Hippel-Lindau (VHL) disease is a dominantly inherited family cancer syndrome characterized by the development of retinal and central nervous system haemangioblastomas, renal cell carcinoma (RCC) and phaeochromocytoma. Specific germline VHL mutations may predispose to haemangioblastomas, RCC and phaeochromocytoma to a varying extent. Although dysregulation of the hypoxia-inducible transcription factor-2 and JunB have been linked to the development of RCC and phaeochromocytoma, respectively, the precise basis for genotype-phenotype correlations in VHL disease have not been defined. To gain insights into the pathogenesis of RCC in VHL disease we compared gene expression microarray profiles in a RCC cell line expressing a Type 1 or Type 2B mutant pVHL (RCC-associated) to those of a Type 2A or 2C mutant (not associated with RCC). We identified 19 differentially expressed novel VHL target genes linked to RCC development. Eight targets were studied in detail by quantitative real-time polymerase chain reaction (three downregulated and five upregulated by wild-type VHL) and for six genes the effect of VHL inactivation was mimicked by hypoxia (but hypoxicinduction of smooth muscle alpha-actin 2 was specific for a RCC cell line). The potential role of four RCCassociated VHL target genes was assessed in vitro. NB thymosin beta (TMSNB) and proteinase-activated receptor 2 (PAR2) (both downregulated by wt pVHL) increased cell growth and motility in a RCC cell line, but aldehyde dehydrogenase (ALDH)1 and ALDH7 had no effect. These findings implicate TMSNB and PAR2 candidate oncogenes in the pathogenesis of VHL-associated RCC.

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Protease-activated receptors mediate apamin-sensitive relaxation of mouse and guinea pig gastrointestinal smooth muscle

Cited by 99 publications

References 31 publications

Involvement of nitric oxide and tachykinins in the effects induced by protease‐activated receptors in rat colon longitudinal muscle

Involvement of nitric oxide and tachykinins in the effects induced by protease‐activated receptors in rat colon longitudinal muscle

Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

Identification of novel VHL targets that are associated with the development of renal cell carcinoma

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