PAR-2 agonists induce contraction of murine small intestine through neurokinin receptors.
Protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor and is expressed throughout the gut. It is well known that PAR-2 participates in the regulation of gastrointestinal motility; however, the results are inconsistent. The present study investigated the effect and mechanism of PAR-2 activation on murine small intestinal smooth muscle function in vitro. Both trypsin and PAR-2-activating peptide SLIGRL induced a small relaxation followed by a concentration-dependent contraction. The sensitivity to trypsin was greater than that to SLIGRL (EC50 = 0.03 vs. 40 microM), but maximal responses were similar (12.3 +/- 1.6 vs. 13.7 +/- 1.3 N/cm2). Trypsin-evoked contraction (1 microM) exhibited a rapid desensitization, whereas the desensitization of response to SLIGRL was less even at high concentration (50 microM). Atropine had no effect on PAR-2 agonist-induced contractions. In contrast, TTX and capsaicin significantly attenuated those contractions, implicating a neurogenic mechanism that may involve capsaicin-sensitive sensory nerves. Furthermore, contractions induced by trypsin and SLIGRL were reduced by neurokinin receptor NK1 antagonist SR-140333 or NK2 antagonist SR-48968 alone or were further reduced by combined application of SR-140333 and SR-48968, indicating the involvement of neurokinin receptors. In addition, desensitizing neurokinin receptors with substance P and/or neurokinin A decreased the PAR-2 agonist-evoked contraction. We concluded that PAR-2 agonists induced a contraction of murine intestinal smooth muscle that was mediated by nerves. The excitatory effect is also dependent on sensory neural pathways and requires both NK1 and NK2 receptors.
Zhao
Aiping
A
Nutritional Requirements and Function Laboratory, Agricultural Research Service, United States Department of Agriculture, Beltsville 20705, USA.
Shea-Donohue
Terez
T
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D005260:Female; D007421:Intestine, Small / Q000737:chemistry / Q000294:innervation / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D015288:Neurokinin A / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D044464:Receptor, PAR-2; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D018179:Receptors, Thrombin / Q000819:agonists* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013373:Substance P / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014357:Trypsin / Q000494:pharmacology
D001549:Benzamides; D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides; D010880:Piperidines; D011812:Quinuclidines; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018179:Receptors, Thrombin; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine; C085215:SR 140333; D013373:Substance P; D013779:Tetrodotoxin; C073839:SR 48968; D015288:Neurokinin A; D014357:Trypsin; D002211:Capsaicin