对人结肠环形平滑肌中5-羟色胺4样受体信号转导机制的进一步研究。

Further investigation into the signal transduction mechanism of the 5-HT4-like receptor in the circular smooth muscle of human colon.

作者信息

McLean P G, Coupar I M

机构信息

School of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy, Monash University, Australia.

出版信息

Br J Pharmacol. 1996 Jun;118(4):1058-64. doi: 10.1111/j.1476-5381.1996.tb15506.x.

DOI:10.1111/j.1476-5381.1996.tb15506.x

PMID:8799582

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1909528/

Abstract

The nature of the receptor coupling mechanism of the 5-hydroxytryptamine4 (5-HT4) receptor in the circular smooth muscle of the human colon has been further investigated. 2. 5-HT stimulated cyclic AMP generation and caused a relaxation in a concentration-dependent fashion, with EC50 values of 175.5 and 274.9 nM respectively. DAU 6236 increased cyclic AMP formation and caused a relaxant effect but was a partial agonist relative to 5-HT. 3. The 5-HT4 receptor antagonist, GR 113808, inhibited cyclic AMP formation and relaxation induced by 5-HT with -log Ki values of 9.1 (cyclic AMP) and 8.9 (relaxation) and apparent pA2 values of 9.2 (cyclic AMP) and 9.5 (relaxation). 4. Ondansetron and methysergide failed to inhibit cyclic AMP formation or the relaxation induced by 5-HT. 5. The phosphodiesterase inhibitor, IBMX, produced a concentration-dependent relaxation (EC50 = 30 microM) and at 1 microM it enhanced the 5-HT-induced relaxation producing a leftward shift of the 5-HT concentration-effect curve with a concentration-ratio of 4.1. Rolipram caused a concentration-dependent relaxation (EC50 = 564.8 nM) and at 200 nm caused a leftward shift of the concentration-effect curve to 5-HT with a concentration-ratio of 5.5. 6. Application of the adenylyl cyclase inhibitor, SQ 22536 (0.1 mM), and the protein kinase inhibitors, H7 (100 nM) and H89 (200 nM), inhibited the relaxant effect of 5-HT inducing a rightward shift of the concentration-effect curve with concentration-ratios of 10.1, 2.7 and 4.2 respectively. 7. Forskolin stimulated cyclic AMP production and caused a relaxation. The maximum relaxant effect of forskolin (6 microM, 13.8 +/- 1.9 cm.s) was not significantly different from the maximum relaxant effect of 5-HT (10 microM, 12.7 +/- 4.9 cm.s). However, the cyclic AMP levels stimulated by forskolin (6 microM, 49.3 +/- 6.6 pmol mg-1) were markedly greater than those stimulated by 5-HT (10 microM, 7.6 +/- 2.0 pmol mg-1). 8. In conclusion, these results indicate that the 5-HT4 receptors of the circular smooth muscle of human colon mediate relaxation and inhibition of spontaneous contractions via activation of adenylyl cyclase, formation of cyclic AMP and activation of protein kinase A.

摘要

对人结肠环形平滑肌中5-羟色胺4（5-HT4）受体的受体偶联机制的性质进行了进一步研究。2. 5-HT以浓度依赖性方式刺激环磷酸腺苷（cAMP）生成并引起松弛，EC50值分别为175.5和274.9 nM。DAU 6236增加cAMP形成并产生松弛作用，但相对于5-HT是部分激动剂。3. 5-HT4受体拮抗剂GR 113808抑制5-HT诱导的cAMP形成和松弛，-log Ki值分别为9.1（cAMP）和8.9（松弛），表观pA2值分别为9.2（cAMP）和9.5（松弛）。4. 昂丹司琼和麦角新碱未能抑制5-HT诱导的cAMP形成或松弛。5. 磷酸二酯酶抑制剂IBMX产生浓度依赖性松弛（EC50 = 30 microM），在1 microM时增强5-HT诱导的松弛，使5-HT浓度-效应曲线向左移位，浓度比为4.1。咯利普兰产生浓度依赖性松弛（EC50 = 564.8 nM），在200 nM时使5-HT浓度-效应曲线向左移位，浓度比为5.5。6. 应用腺苷酸环化酶抑制剂SQ 22536（0.1 mM）以及蛋白激酶抑制剂H7（100 nM）和H89（200 nM），抑制5-HT的松弛作用，使浓度-效应曲线向右移位，浓度比分别为10.1、2.7和4.2。7. 福斯高林刺激cAMP产生并引起松弛。福斯高林（6 microM，13.8±1.9 cm.s）的最大松弛作用与5-HT（10 microM，12.7±4.9 cm.s）的最大松弛作用无显著差异。然而，福斯高林（6 microM，49.3±6.6 pmol mg-1）刺激的cAMP水平明显高于5-HT（10 microM，7.6±2.0 pmol mg-1）刺激的水平。8. 总之，这些结果表明，人结肠环形平滑肌的5-HT4受体通过激活腺苷酸环化酶、形成cAMP和激活蛋白激酶A介导松弛和抑制自发收缩。