Pharmacological inhibition of TRPM4 hyperpolarizes vascular smooth muscle
Pharmacological inhibition of TRPM4 hyperpolarizes vascular smooth muscle
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DOI：
10.1152/ajpcell.00269.2010
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发表时间：
2010-11-01
影响因子：
5.5
通讯作者：
Earley, Scott
中科院分区：
文献类型：
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作者：
Gonzales, Albert L.;Garcia, Zarine I.;Earley, Scott
冈萨雷斯AL，加西亚ZI，安贝格GC，厄利S. TRPM 4的药理学抑制使血管平滑肌超极化。美国生理学杂志细胞生理学299：C1195-C1202，2010年。首次发表于2010年9月8日; doi：10.1152/ajpcell.00269.2010。血管平滑肌细胞的收缩状态由膜电位的微小变化调节，膜电位的微小变化门控电压依赖性钙通道。Melastatin瞬时受体电位（TRP）通道TRPM 4是压力诱导的膜去极化和动脉收缩的关键介质。最近的一项研究表明，三环化合物9-菲咯抑制TRPM 4，但不抑制相关的通道TRPM 5。本研究探讨了9-菲咯的特异性以及该化合物对压力诱导的平滑肌去极化和动脉收缩的影响。膜片钳电生理学显示，9-菲咯阻断天然TRPM 4电流在新鲜分离的平滑肌细胞中的浓度依赖性的方式（IC 50 = 10.6 μ M）。9-邻菲咯（30 μ M）对表达重组TRPC 3或TRPC 6通道的人胚肾细胞的最大诱发电流没有影响。大电导Ca 2+激活的K+，电压依赖性K+，内向整流K+，电压依赖性Ca 2+通道活性在本地脑动脉肌细胞没有改变9-菲咯（30 μ M）的管理。使用细胞内微电极记录加压至70 mmHg的离体脑动脉中的平滑肌膜电位，我们发现9-菲咯（30 μ M）可逆地使膜从近似-40 mV超极化至近似-70 mV。此外，我们发现，当血管暴露于9-菲咯时，肌源性张力被可逆地消除。这些数据表明，9-菲可用于研究TRPM 4在血管平滑肌细胞中的功能意义，并且TRPM 4是平滑肌细胞膜去极化和动脉收缩响应于管腔内压力的重要调节剂。
Gonzales AL, Garcia ZI, Amberg GC, Earley S. Pharmacological inhibition of TRPM4 hyperpolarizes vascular smooth muscle. Am J Physiol Cell Physiol 299: C1195-C1202, 2010. First published September 8, 2010; doi:10.1152/ajpcell.00269.2010.-The contractile state of vascular smooth muscle cells is regulated by small changes in membrane potential that gate voltage-dependent calcium channels. The melastatin transient receptor potential (TRP) channel TRPM4 is a critical mediator of pressure-induced membrane depolarization and arterial constriction. A recent study shows that the tricyclic compound 9-phenanthrol inhibits TRPM4, but not the related channel TRPM5. The current study investigated the specificity of 9-phenanthrol and the effects of the compound on pressure-induced smooth muscle depolarization and arterial constriction. Patch-clamp electrophysiology revealed that 9-phenanthrol blocks native TRPM4 currents in freshly isolated smooth muscle cells in a concentration-dependent manner (IC50 = 10.6 mu M). 9-Phenanthrol (30 mu M) had no effect on maximum evoked currents in human embryonic kidney cells expressing recombinant TRPC3 or TRPC6 channels. Large-conductance Ca2+-activated K+, voltage-dependent K+, inwardly rectifying K+, and voltage-dependent Ca2+ channel activity in native cerebral artery myocytes was not altered by administration of 9-phenanthrol (30 mu M). Using intracellular microelectrodes to record smooth muscle membrane potential in isolated cerebral arteries pressurized to 70 mmHg, we found that 9-phenanthrol (30 mu M) reversibly hyperpolarized the membrane from similar to -40 mV to similar to -70 mV. In addition, we found that myogenic tone was reversibly abolished when vessels were exposed to 9-phenanthrol. These data demonstrate that 9-phenanthrol is useful for studying the functional significance of TRPM4 in vascular smooth muscle cells and that TRPM4 is an important regulator of smooth muscle cell membrane depolarization and arterial constriction in response to intraluminal pressure.