Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, 89557, USA.
Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, South Korea.
Sci Rep. 2022 Oct 6;12(1):16746. doi: 10.1038/s41598-022-21285-2.
Protease-activated receptor-1 (PAR1) is highly expressed in murine colonic smooth muscles. Responses to PAR1 activation are complex and result from responses in multiple cell types. We investigated whether PAR1 responses are altered in inflamed colon induced by dextran sodium sulfate (DSS)-treatment. Colitis was induced in C57BL/6 mice by administration of 3% DSS in drinking water for 7 days. Measurements of isometric force, transmembrane potentials from impaled smooth muscle cells, quantitative PCR and Western blots were performed. Thrombin, an activator of PAR1, caused transient hyperpolarization and relaxation of untreated colons, but these responses decreased in DSS-treated colons. Apamin caused depolarization and increased contractions of muscles from untreated mice. This response was decreased in DSS-treated colons. Expression of Kcnn3 and Pdgfra also decreased in DSS-treated muscles. A second phase of thrombin responses is depolarization and increased contractions in untreated muscles. However, thrombin did cause depolarization in DSS-treated colon, yet it increased colonic contractions. The latter effect was associated with enhanced expression of MYPT1 and CPI-17. The propagation velocity and frequency of colonic migrating motor complexes in DSS-treated colon was significantly higher compared to control colons. In summary, DSS treatment causes loss of transient relaxations due to downregulation of SK3 channels in PDGFRα cells and may increase contractile responses due to increased Ca sensitization of smooth muscle cells via PAR1 activation.
蛋白酶激活受体-1（PAR1）在鼠结肠平滑肌中高度表达。PAR1 激活的反应是复杂的，是多种细胞类型反应的结果。我们研究了在葡聚糖硫酸钠（DSS）处理诱导的炎症结肠中，PAR1 反应是否发生改变。通过在饮用水中给予 3%的 DSS 来诱导 C57BL/6 小鼠结肠炎，持续 7 天。进行等长力测量、刺穿平滑肌细胞的跨膜电位、定量 PCR 和 Western blot。凝血酶是 PAR1 的激活剂，可引起未处理结肠的短暂超极化和松弛，但在 DSS 处理的结肠中这些反应减少。阿帕米可引起未处理小鼠肌肉去极化和收缩增加。在 DSS 处理的结肠中，这种反应减少。Kcnn3 和 Pdgfra 的表达也在 DSS 处理的肌肉中减少。凝血酶的第二个反应阶段是未处理肌肉中的去极化和收缩增加。然而，凝血酶确实在 DSS 处理的结肠中引起去极化，但它增加了结肠收缩。后一种作用与 MYPT1 和 CPI-17 的表达增强有关。DSS 处理的结肠中的结肠移行性运动复合波的传播速度和频率明显高于对照结肠。总之，DSS 处理导致瞬时松弛丧失，这是由于 PDGFRα 细胞中 SK3 通道下调引起的，并且可能通过 PAR1 激活增加平滑肌细胞的 Ca2+敏感性而增加收缩反应。
