Department of Pharmacology, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan.
Eur J Pharmacol. 2012 Feb 29;677(1-3):123-30. doi: 10.1016/j.ejphar.2011.12.005. Epub 2011 Dec 19.
An involvement of signal transduction other than phosphatidylinositol turnover in thromboxane A(2) receptor (TP receptor)-mediated vascular contraction was investigated in rat aorta. The contraction induced by U46619, a TP receptor agonist, at low concentrations (≤ 30 nM) was partially inhibited by verapamil, an inhibitor of voltage-dependent Ca(2+) channels (VDCC), and was further diminished in Ca(2+)-free solution. Twenty nanomolar of U46619 induced contraction and elevation of intracellular Ca(2+) concentration (Ca(2+)), which were consisted of two phases; slowly developing first phase followed by quickly rising second phase. The second phase was inhibited by verapamil, and all the Ca(2+) response was abolished in Ca(2+)-free solution. The contraction and Ca(2+) elevation induced by 20 nM U46619 were not inhibited by U73122, an inhibitor of phosphatidylinositol-specific phospholipase C, or GF109203X, a protein kinase C inhibitor, but were abolished by D609, an inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC). However, D609 had no effect on those induced by 1 μM phenylephrine. The U46619-induced responses were also partially inhibited by cation channel blockers, 2-APB and LOE908. The inhibition by LOE908 was abolished in the presence of verapamil, suggesting that LOE908-sensitive cation channels lead to the activation of VDCC by depolarizing plasma membrane. In contrast, 2-APB further diminished the U46619-induced Ca(2+) elevation in the presence of verapamil. In conclusion, TP receptor stimulation is suggested to be coupled with PC-PLC. Diacylglycerol produced by PC-PLC seems to activate two types of cation channels independently of PKC, which in turn leads to VDCC-dependent and independent Ca(2+) influx, thereby eliciting contraction.
研究了血小板衍生的血栓烷 A2 受体（TP 受体）介导的血管收缩中信号转导途径除磷脂酰肌醇代谢之外的其他途径。在低浓度（≤30 nM）时，TP 受体激动剂 U46619 诱导的收缩部分被电压依赖性钙通道（VDCC）抑制剂维拉帕米抑制，并且在无钙溶液中进一步减少。20 nM U46619 诱导收缩和细胞内钙浓度升高([Ca2+]i)，其由两个阶段组成；缓慢发展的第一阶段，随后是快速上升的第二阶段。第二阶段被维拉帕米抑制，并且在无钙溶液中所有的[Ca2+]i 反应都被消除。20 nM U46619 诱导的收缩和[Ca2+]i 升高不受 U73122（一种磷脂酰肌醇特异性磷脂酶 C 抑制剂）或 GF109203X（一种蛋白激酶 C 抑制剂）的抑制，但被 D609（一种磷脂酰胆碱特异性磷脂酶 C（PC-PLC）抑制剂）抑制。然而，D609 对 1 μM 苯肾上腺素诱导的收缩没有影响。U46619 诱导的反应也被阳离子通道阻滞剂 2-APB 和 LOE908 部分抑制。LOE908 的抑制在维拉帕米存在时被消除，表明 LOE908 敏感的阳离子通道通过去极化质膜导致 VDCC 的激活。相反，2-APB 在维拉帕米存在时进一步减少 U46619 诱导的[Ca2+]i 升高。总之，TP 受体刺激被认为与 PC-PLC 偶联。PC-PLC 产生的二酰基甘油似乎独立于 PKC 激活两种类型的阳离子通道，这反过来导致 VDCC 依赖和非依赖的 Ca2+内流，从而引起收缩。
