Voltage- and temperature-dependent activation of TRPV3 channels is potentiated by receptor-mediated PI(4,5)P2 hydrolysis.
Voltage- and temperature-dependent activation of TRPV3 channels is potentiated by receptor-mediated PI(4,5)P2 hydrolysis.
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DOI：
10.1085/jgp.200910388
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发表时间：
2011-03
期刊：
影响因子：
--
通讯作者：
Ramsey IS
中科院分区：
文献类型：
--
作者：
Doerner JF;Hatt H;Ramsey IS
TRPV3是一种热敏通道，在皮肤角质形成细胞中强烈表达，可被无害的热加热、膜去极化和化学激动剂（如2-氨基乙氧基二苯硼酸盐、香豆醇和樟脑）激活。TRPV3调节啮齿动物的感觉热转导、毛发生长和对皮炎的易感性，但控制角化细胞中TRPV3通道活性的分子机制尚不清楚。我们在这里表明，受体介导的膜脂磷脂酰肌醇（4,5）二磷酸（PI(4,5)P2）的破坏调节了原代人皮肤角质形成细胞中天然TRPV3通道的活性，并在稳定表达毒菌碱m1型乙酰胆碱受体的hek -293衍生细胞系中表达了TRPV3。刺激PI(4,5)P2水解或药理抑制PI 4激酶以阻断PI(4,5)P2合成，通过引起通道打开的电压依赖性的负位移，增加电压无关电流的比例并导致在较低温度下发生热激活，从而增强TRPV3电流。切除斑块中单个TRPV3通道的活性通过PI(4,5)P2缺失而增强，并且与相关的磷脂酰肌醇磷酸相比，PI(4,5)P2选择性地降低。TRP结构域基本残基的中和突变消除了PI(4,5)P2对通道功能的影响，表明PI(4,5)P2直接与特定的蛋白基序相互作用，降低了TRPV3通道打开的概率。PI(4,5) p2依赖性TRPV3活性的调节是角化细胞信号级联反应的一种有吸引力的急性调节机制，该信号级联反应控制细胞增殖和自分泌和旁分泌因子的释放。
TRPV3 is a thermosensitive channel that is robustly expressed in skin keratinocytes and activated by innocuous thermal heating, membrane depolarization, and chemical agonists such as 2-aminoethyoxy diphenylborinate, carvacrol, and camphor. TRPV3 modulates sensory thermotransduction, hair growth, and susceptibility to dermatitis in rodents, but the molecular mechanisms responsible for controlling TRPV3 channel activity in keratinocytes remain elusive. We show here that receptor-mediated breakdown of the membrane lipid phosphatidylinositol (4,5) bisphosphate (PI(4,5)P2) regulates the activity of both native TRPV3 channels in primary human skin keratinocytes and expressed TRPV3 in a HEK-293–derived cell line stably expressing muscarinic M1-type acetylcholine receptors. Stimulation of PI(4,5)P2 hydrolysis or pharmacological inhibition of PI 4 kinase to block PI(4,5)P2 synthesis potentiates TRPV3 currents by causing a negative shift in the voltage dependence of channel opening, increasing the proportion of voltage-independent current and causing thermal activation to occur at cooler temperatures. The activity of single TRPV3 channels in excised patches is potentiated by PI(4,5)P2 depletion and selectively decreased by PI(4,5)P2 compared with related phosphatidylinositol phosphates. Neutralizing mutations of basic residues in the TRP domain abrogate the effect of PI(4,5)P2 on channel function, suggesting that PI(4,5)P2 directly interacts with a specific protein motif to reduce TRPV3 channel open probability. PI(4,5)P2-dependent modulation of TRPV3 activity represents an attractive mechanism for acute regulation of keratinocyte signaling cascades that control cell proliferation and the release of autocrine and paracrine factors.
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