Protein kinase C regulates vascular myogenic tone through activation of TRPM4
Protein kinase C regulates vascular myogenic tone through activation of TRPM4
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DOI：
10.1152/ajpheart.01286.2006
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发表时间：
2007-06-01
影响因子：
4.8
通讯作者：
Brayden, Joseph E.
中科院分区：
文献类型：
--
作者：
Earley, Scott;Straub, Stephen V.;Brayden, Joseph E.
蛋白激酶C通过激活TRPM 4调节血管肌源性张力。美国生理学杂志心脏循环生理学292：H2613-H2622，2007年。首次发表于2007年2月9日：doi：10.1152/ajpheart.01286.2006。- 肌源性血管收缩是由压力诱导的血管平滑肌细胞去极化和通过电压依赖性Ca 2+通道的Ca 2+内流引起的，该过程可通过抑制蛋白激酶C（PKC）而显著减弱。最近的研究表明，melastatin瞬时受体电位（TRP）通道TRPM 4是压力诱导的脑动脉平滑肌去极化和收缩的关键介质。很有趣。PKC活性通过增加通道对细胞内Ca 2+的敏感性来增强在培养细胞中表达的克隆TRPM 4通道的激活。因此，我们假设TRPM 4的PKC依赖性激活可能是血管肌源性张力的关键介质。我们在这里报告，PKC抑制衰减压力引起的脑血管收缩和刺激PKC活性与佛波酯12-肉豆蔻酸酯13-乙酸酯（PMA）增强了肌源性张力的发展。拟合新鲜分离的脑动脉肌细胞，我们确定了一个Ca 2+依赖性，快速失活，外向整流，伊比利亚毒素不敏感的阳离子电流与表达的TRPM 4通道的性质相似。用PMA刺激PKC活性增加了血管平滑肌细胞中该电流的细胞内Ca 2+敏感性。为了验证TRPM 4作为PKC调节的靶点，使用反义技术来抑制TRPM 4在分离的脑动脉中的表达。在这种情况下。与对照相比，在用反义寡核苷酸处理的动脉细胞中TRPM 4样电流的大小减少。将TRPM 4鉴定为负责PKC激活电流的分子实体。此外。与对照相比，用TRPM 4反义寡核苷酸处理的动脉中PKC诱导的平滑肌细胞去极化和血管收缩的程度显著降低。我们的结论是，PKC依赖的TRPM 4活性的调节有助于脑动脉肌源性张力的控制。
Protein kinase C regulates vascular myogenic tone through activation of TRPM4. Am J Physiol Heart Circ Physiol 292: H2613-H2622, 2007. First published February 9, 2007: doi: 10.1152/ajpheart.01286.2006. - Myogenic vasoconstriction results from pressure-induced vascular smooth Muscle Cell depolarization and Ca2+ influx via voltage-dependent Ca2+ channels, a process that is significantly attenuated by inhibition of protein kinase C (PKC). It was recently reported that the melastatin transient receptor potential (TRP) channel TRPM4 is a critical mediator of pressure-induced smooth Muscle depolarization and constriction in cerebral arteries. Interestingly. PKC activity enhances the activation of cloned TRPM4 channels expressed ill Cultured cells by increasing sensitivity of the channel to intracellular Ca2+. Thus We Postulated that PKC-dependent activation of TRPM4 might be a critical mediator of vascular myogenic tone. We report here that PKC inhibition attenuated pressure-induced constriction of cerebral vessels and that stimulation of PKC activity with phorbol 12-myristate 13-acetate (PMA) enhanced the development of myogenic tone. fit freshly isolated cerebral artery myocytes, we identified a Ca2+-dependent, rapidly inactivating, outwardly rectifying, iberiotoxin-insensitive cation current with properties similar to those of expressed TRPM4 channels. Stimulation of PKC activity with PMA increased the intracellular Ca2+ sensitivity of this current in vascular smooth muscle cells. To validate TRPM4 as a target of PKC regulation, antisense technology was used to Suppress TRPM4 expression in isolated cerebral arteries. Under these conditions. the magnitude of TRPM4-like Currents was diminished in cells from arteries treated with antisense oligo-nucleotides compared with controls. identifying TRPM4 as the molecular entity responsible for the PKC-activated current. Furthermore. the extent of PKC-induced smooth Muscle cell depolarization and vasoconstriction was significantly decreased in arteries treated with TRPM4 antisense oligonucleotides compared with controls. We conclude that PKC-dependent regulation of TRPM4 activity contributes to the control of cerebral artery myogenic tone.