The protease-activated receptor (PAR)-2 is highly expressed in endothelial cells and vascular smooth muscle cells. It plays a crucial role in regulating blood pressure via the modulation of peripheral vascular tone. Although several mechanisms have been suggested to explain PAR-2-induced hypotension...
The protease-activated receptor (PAR)-2 is highly expressed in endothelial cells and vascular smooth muscle cells. It plays a crucial role in regulating blood pressure via the modulation of peripheral vascular tone. Although several mechanisms have been suggested to explain PAR-2-induced hypotension, the precise mechanism remains to be elucidated. To investigate this possibility, we investigated the effects of PAR-2 activation on N-type $Ca^{2+}$ currents ($I_{Ca-N}$) in isolated neurons of the celiac ganglion (CG), which is involved in the sympathetic regulation of mesenteric artery vascular tone. PAR-2 agonists irreversibly diminished voltage-gated $Ca^{2+}$ currents ($I_{Ca}$), measured using the patch-clamp method, in rat CG neurons, whereas thrombin had little effect on $I_{Ca}$. This PAR-2-induced inhibition was almost completely prevented by ${\omega}$-CgTx, a potent N-type $Ca^{2+}$ channel blocker, suggesting the involvement of N-type $Ca^{2+}$ channels in PAR-2-induced inhibition. In addition, PAR-2 agonists inhibited $I_{Ca-N}$ in a voltage-independent manner in rat CG neurons. Moreover, PAR-2 agonists reduced action potential (AP) firing frequency as measured using the current-clamp method in rat CG neurons. This inhibition of AP firing induced by PAR-2 agonists was almost completely prevented by ${\omega}$-CgTx, indicating that PAR-2 activation may regulate the membrane excitability of peripheral sympathetic neurons through modulation of N-type $Ca^{2+}$ channels. In conclusion, the present findings demonstrate that the activation of PAR-2 suppresses peripheral sympathetic outflow by modulating N-type $Ca^{2+}$ channel activity, which appears to be involved in PAR-2-induced hypotension, in peripheral sympathetic nerve terminals.
The protease-activated receptor (PAR)-2 is highly expressed in endothelial cells and vascular smooth muscle cells. It plays a crucial role in regulating blood pressure via the modulation of peripheral vascular tone. Although several mechanisms have been suggested to explain PAR-2-induced hypotension, the precise mechanism remains to be elucidated. To investigate this possibility, we investigated the effects of PAR-2 activation on N-type $Ca^{2+}$ currents ($I_{Ca-N}$) in isolated neurons of the celiac ganglion (CG), which is involved in the sympathetic regulation of mesenteric artery vascular tone. PAR-2 agonists irreversibly diminished voltage-gated $Ca^{2+}$ currents ($I_{Ca}$), measured using the patch-clamp method, in rat CG neurons, whereas thrombin had little effect on $I_{Ca}$. This PAR-2-induced inhibition was almost completely prevented by ${\omega}$-CgTx, a potent N-type $Ca^{2+}$ channel blocker, suggesting the involvement of N-type $Ca^{2+}$ channels in PAR-2-induced inhibition. In addition, PAR-2 agonists inhibited $I_{Ca-N}$ in a voltage-independent manner in rat CG neurons. Moreover, PAR-2 agonists reduced action potential (AP) firing frequency as measured using the current-clamp method in rat CG neurons. This inhibition of AP firing induced by PAR-2 agonists was almost completely prevented by ${\omega}$-CgTx, indicating that PAR-2 activation may regulate the membrane excitability of peripheral sympathetic neurons through modulation of N-type $Ca^{2+}$ channels. In conclusion, the present findings demonstrate that the activation of PAR-2 suppresses peripheral sympathetic outflow by modulating N-type $Ca^{2+}$ channel activity, which appears to be involved in PAR-2-induced hypotension, in peripheral sympathetic nerve terminals.
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제안 방법
, 2004). As for the irreversible nature of the suppression of ICa-N by PAR-2 activation, we cannot suggest a feasible explanation based on the results obtained from this study. PAR-2 activated by irreversible proteolysis that results in continuous stimulation; however, cleaved PAR-2 is known to be rapidly ubiquitinated at the C-terminus, which mediates downregulation of PAR-2 to terminate signaling.
Data are presented as the means ±SEM, with the number of experiments denoted within parentheses. The concentration-response curves of trypsin and SR-NH2 for ICa inhibition were calculated by fitting the data to a single-site binding isotherm with least-squares nonlinear regression using Prism 5.0 (GraphPad, USA). We used unpaired Student’s t-tests to compare data from two groups.
To investigate this hypothesis, we directly examined the effect of PAR-2 activation on N-type Ca2+ currents in isolated neurons of the celiac ganglion (CG), which regulates vascular sympathetic tone of the mesenteric artery.
대상 데이터
Male Sprague-Dawley rats were used in all of the experiments conducted. They were purchased from Orient Co.
데이터처리
We used unpaired Student’s t-tests to compare data from two groups.
성능/효과
In conclusion, the present findings demonstrate that the activation of PAR-2 suppresses peripheral sympathetic outflow by modulating N-type Ca2+ channel activity in peripheral sympathetic nerve terminals, which appear to be involved in PAR-2- induced hypotension.
참고문헌 (35)
al-Ani B. Saifeddine M. Hollenberg M.D. 1995 Detection of functional receptors for the proteinase-activated-receptor-2-activating polypeptide, SLIGRL-NH 2 , in rat vascular and gastric smooth muscle. Can. J. Physiol. Pharmacol. 73 1203 1207 8564891
Carrier G.O. Ikeda S.R. 1992 TTX-sensitive Na + channels and Ca 2+ channels of the L- and N-type underlie the inward current in acutely dispersed coeliac-mesenteric ganglia neurons of adult rats. Pflugers Arch. 421 7 16 1321408
Cheung W.M. Andrade-Gordon P. Derian C.K. Damiano B.P. 1998 Receptor-activating peptides distinguish thrombin receptor (PAR-1) and protease activated receptor 2 (PAR-2) mediated hemodynamic responses in vivo Can. J. Physiol. Pharmacol. 76 16 25 9564545
Chien E.K. Sweet L. Phillippe M. Marietti S. Kim T.T. Wolff D.A. Thomas L. Bieber E 2003 Protease-activated receptor isoform expression in pregnant and nonpregnant rat myometrial tissue. J. Soc. Gynecol. Investig. 10 460 468
Chung S. Ahn D.S. Kim Y.H. Kim Y.S. Joeng J.H. Nam T.S. 2010 Modulation of N-type calcium currents by presynaptic imidazoline receptor activation in rat superior cervical ganglion neurons. Exp. Physiol. 95 982 993 20696781
Cicala C. Pinto A. Bucci M. Sorrentino R. Walker B. Harriot P. Cruchley A. Kapas S. Howells G.L. Cirino G. 1999 Protease-actibated receptor-2 involvement in hypotension in normal and endotoxemic rats in vivo Circulation 99 2590 2597 10330393
Cicala C. Morello S. Santagada V. Caliendo G. Sorrentino L. Cirino G 2001 Pharmacological dissection of vascular effects caused by activation of protease-activated receptors 1 and 2 in anesthetized rats. FASEB J. 15 1433 1435 11387248
Damiano B.P. Cheung W.M. Santulli R.J. Fung-Leung W.P. Ngo K. Ye R.D. Darrow A.L. Derian C.K. de Garavilla L. Andrade-Gordon P 1999 Cardiovascular responses mediated by protease-activated receptor-2 (PAR-2) and thrombin receptor (PAR-1) are distinguished in mice deficient in PAR-2 or PAR-1 J. Pharmacol. Exp. Ther. 288 671 678 9918574
Elmslie K.S. Zhou W. Jones S.W. 1990 LHRH and GTP-gamma-S modify calcium current activation in bullfrog sympathetic neurons Neuron 5 75 80 2164405
Emilsson K. Wahlestedt C. Sun M.K. Nystedt S. Owman C. Sundelin J 1997 Vascular effects of proteinase-activated receptor 2 agonist peptide. J. Vasc. Res. 34 267 272 9256086
Emilsson V. Arch J.R. de Groot R.P. Lister C.A. Cawthorne M.A. 1999 Leptin treatment increases suppressors of cytokine signaling in central and peripheral tissues. FEBS Lett. 455 170 174 10428495
Hollenberg M.D. Saifeddine M. al-Ani B 1996 Proteinase-activated receptor-2 in rat aorta: structural requirements for agonist activity of receptor-activating peptides. Mol. Pharmacol. 49 229 233 8632754
Hwa J.J. Ghibaudi L. Williams P. Chintala M. Zhang R. Chatterjee M. Sybertz E 1996 Evidence for the presence of a proteinase-activated receptor distinct from the thrombin receptor in vascular endothelial cells. Circ. Res. 78 581 588 8635215
Kawabata A. Kuroda R. Hollenberg M.D. 1999 Physiology of protease-activated receptors (PARs): involvement of PARs in digestive functions Nihon Yakurigaku Zasshi 114 173P 179P
Kawabata A. Nakaya Y. Kuroda R. Wakisaka M. Masuko T. Nishikawa H. Kawai K 2003 Involvement of EDHF in the hypotension and increased gastric mucosal blood flow caused by PAR-2 activation in rats. Br. J. Pharmacol. 140 247 254 12970102
McGuire J.J. Dai J. Andrade-Gordon P. Triggle C.R. Hollenberg M.D. 2002 Proteinase-activated receptor-2 (PAR2): vascular effects of a PAR2-derived activating peptide via a receptor different than PAR2 J. Pharmacol. Exp. Ther. 303 985 992 12438518
Molderings G.J. Likungu J. Gothert M. 2000 N-Type calcium channels control sympathetic neurotransmission in human heart atrium Circulation 101 403 407 10653832
Myers A.C. 1998 Ca 2+ and K + currents regulate accommodation and firing frequency in guinea pig bronchial ganglion neurons. Am. J. Physiol. 275 L357 364 9700097
Nystedt S. Emilsson K. Wahlestedt C. Sundelin J. 1994 Molecular cloning of a potential proteinase activated receptor. Proc. Natl. Acad. Sci. USA 91 9208 9212 7937743
Roy S.S. Saifeddine M. Loutzenhiser R. Triggle C.R. Hollenberg M.D. 1998 Dual endothelium-dependent vascular activities of proteinase-activated receptor-2-activating peptides: evidence for receptor heterogeneity. Br. J. Pharmacol. 123 1434 1440 9579740
Saifeddine M. al-Ani B. Cheng C.H. Wang L. Hollenberg M.D. 1996 Rat proteinase-activated receptor-2 (PAR-2): cDNA sequence and activity of receptor-derived peptides in gastric and vascular tissue. Br. J. Pharmacol. 118 521 530 8762073
Shapiro M.S. Wollmuth L.P. Hille B 1994 Modulation of Ca 2+ channels by PTX-sensitive G-proteins is blocked by N-ethylmaleimide in rat sympathetic neurons. J. Neurosci. 14 7109 7116 7525895
Shimosawa T. Takano K. Ando K. Fujita T. 2004 Magnesium inhibits norepinephrine release by blocking N-type calcium channels at peripheral sympathetic nerve endings Hypertension 44 897 902 15477382
Sobey C.G. Cocks T.M. 1998 Activation of protease-activated receptor-2 (PAR-2) elicits nitric oxide-dependent dilatation of the basilar artery in vivo Stroke 29 1439 1444 9660401
Sosa Z.Y. Casais M. Rastrilla A.M. Aguado L 2000 Adrenergic influences on coeliac ganglion affect the release of progesterone from cycling ovaries: characterisation of an in vitro system. J. Endocrinol. 166 307 318 10927620
Whorlow S.L. Angus J.A. Wright C.E. 1996 SELECTIVITY OF ω-CONOTOXIN GVIA FOR N-TYPE CALCIUM CHANNELS IN RAT ISOLATED SMALL MESENTERIC ARTERIES. Clin. Exp. Pharmacol. Physiol. 23 16 21 8713491
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