Alimentary TractProtease-activated receptors mediate apamin-sensitive relaxation of mouse and guinea pig gastrointestinal smooth muscle☆,☆☆
Section snippets
Tissue preparation
Male Balb-c mice (20–30 g) and Hartley Tri-colored male and female guinea pigs (200–400 g) were killed by cervical dislocation with approval from the University of Melbourne Animal Experimentation Ethics Committee. The mouse stomach was isolated and cleared of its contents, and the fundic region was cut into two longitudinal strips (3 × 10 mm). Some strips had the mucosa removed by careful dissection under a microscope. Approximately 5-mm-long segments of the taenia coli were removed with
Mouse gastric fundus
Thrombin (0.3 U/mL) and trypsin (0.3 U/mL) caused biphasic responses in the mouse gastric fundus that consisted of an initial relaxation with maxima of 31.7% ± 3.7% (n = 7) and 34.7% ± 5.5% (n = 8) followed by contractions of 11.4% ± 3.4% (n = 7) and 31.7% ± 7.1% (n = 8), respectively (Figure 1).
Discussion
Although Corvera et al.13 showed that PAR-2 activation inhibited spontaneous contractile activity in the rat isolated distal colon, our study is the first to show that both PAR-1 and PAR-2 mediate direct relaxation of gastrointestinal smooth muscle and that these relaxations are able to largely mask previously reported contractile effects of both enzymes (thrombin and trypsin) and peptide activators of PARs in the gut.7, 17, 18 Our study also shows that relaxations to the PAR-1 and PAR-2
References (33)
- et al.
Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation
Cell
(1991) - et al.
Interactions of mast cell tryptase with thrombin receptors and PAR-2
J Biol Chem
(1997) - et al.
Ligand cross-reactivity within the protease-activated receptor family
J Biol Chem
(1996) - et al.
The pharmacology of intracellular Ca2+-release channels
- et al.
Ca2+ sparks and Ca2+ waves activate different Ca2+-dependent ion channels in single myocytes from rat portal vein
Cell Calcium
(1996) - et al.
Receptor and G-protein-mediated responses to thrombin in HEL cells
J Biol Chem
(1991) - et al.
The thrombin receptor second cytoplasmic loop confers coupling to Gq-like G proteins in chimeric receptors
J Biol Chem
(1997) - et al.
Endothelial cell thrombin receptors and PAR-2: two protease-activated receptors located in a single cellular environment
J Biol Chem
(1997) - et al.
The inhibitory action of suramin on the P2-purinoceptor response in smooth muscle cells of guinea-pig taenia caeci
Eur J Pharmacol
(1989) - et al.
Effect of apamin on the electrical responses of smooth muscle to adenosine 5'-triphosphate and to non-adrenergic, non-cholinergic nerve stimulation
Neuroscience
(1980)
A comparison between ATP and bradykinin as possible mediators of the responses of smooth muscle to non-adrenergic, non-cholinergic nerves
Eur J Pharmacol
Non-adrenergic non-cholinergic (NANC) transmission to smooth muscle: 35 years on
Prog Neurobiol
Protease-activated receptors start a family
Proc Natl Acad Sci USA
Molecular cloning of a potential proteinase activated receptor
Proc Natl Acad Sci USA
Protease-activated receptor 3 is a second thrombin receptor in humans
Nature
Cloning and characterization of human protease-activated receptor 4
Proc Natl Acad Sci USA
Cited by (97)
Proteinase-activated receptors regulate intestinal functions in a segment-dependent manner in rats
2022, European Journal of PharmacologyTrypsin-induced biphasic regulation of tone in the porcine lower esophageal sphincter
2015, European Journal of PharmacologyCitation Excerpt :PKC, ROK, ERK1/2 and p38MAPK are known to inhibit the activity of myosin light chain phosphatase, thus contributing to smooth muscle contraction (Eto et al., 1995; Ihara et al., 2007; Kimura et al., 1996). Regulation of gastrointestinal contractility by trypsin/PARs has been reported in stomach, small intestine and colon (Cocks et al., 1999; Kawabata et al., 1999; Mule et al., 2002). However, limited information is available regarding the regulatory role of trypsin in the function of esophagus.
Proteinase-activated receptor-1 (PAR1) and PAR2 mediate relaxation of guinea pig internal anal sphincter
2014, Regulatory PeptidesCitation Excerpt :In the gastrointestinal tract, PAR1 and PAR2 stimulate contraction of the human esophagus [6], guinea pig and rat stomach [9,10], human and guinea pig gallbladder [12,13] as well as rat colon [15]. In addition, PAR1 and PAR2 activation evokes relaxation of the guinea pig lower esophageal sphincter [7] and guinea pig colon [8]. Both PAR1 and PAR2 elicit a dual action, i.e., relaxation followed by contraction, in the mouse gastric fundus [8] and rat duodenum [11].
Effects of trypsin, thrombin and proteinase-activated receptors on guinea pig common bile duct motility
2012, Regulatory PeptidesCitation Excerpt :PARs are found in various tissues, including the gastrointestinal tract [1–4,6]. PAR1, PAR2 and PAR4 modulate the gastrointestinal motility and secretion [1,6–14]. In the human and guinea pig gallbladder, both PAR1 and PAR2 mediate contraction; however, PAR4 activation does not alter gallbladder motility [10,11].
- ☆
Address requests for reprints to: Thomas M. Cocks, Ph.D., Department of Pharmacology, Tri-radiate Building, Parkville, Victoria 3052, Australia. e-mail: [email protected]; fax: (61) 3-934-71452.
- ☆☆
Supported by the National Health and Medical Research Council of Australia.