Interaction with phosphoinositides confers adaptation onto the TRPV1 pain receptor.
Interaction with phosphoinositides confers adaptation onto the TRPV1 pain receptor.
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DOI：
10.1371/journal.pbio.1000046
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发表时间：
2009-02-24
期刊：
影响因子：
9.8
通讯作者：
Qin F
中科院分区：
文献类型：
--
作者：
Yao J;Qin F
适应是许多感官系统的共同特征。但它对痛感的出现仍然难以捉摸。在这里，我们在受体水平上解决这个问题，并表明辣椒素离子通道TRPV1，它介导周围神经末梢的伤害性感受，具有适应感觉反应所必需的特性。通道开放后钙离子内流引起激动剂敏感性的显著变化(∼的14倍)，但不改变最大可获得电流。这种变化足以使通道对正常饱和的浓度没有反应，留下了通道在脱敏后不再起作用的概念。通过膜片钳记录和全内反射荧光(TIRF)成像，发现钙离子内流引起的磷脂酰肌醇4，5-二磷酸(PIP2)的耗竭具有与电流失敏同步的快速时程。耗竭的程度与雷帕霉素诱导的PIP2 5-磷酸酶激活的程度相当，这也导致激动剂敏感性显著降低，而不影响最大反应。这些结果支持PIP2耗竭对TRPV1脱敏的显著贡献，并提示这种适应可能是通过该通道的钙内流的一种生理功能。感官感受器可以调整它们对持续变化的刺激的敏感性，这一过程被称为适应。适应已经在视觉、听觉和嗅觉系统中得到了广泛的研究，但它是否也发生在痛觉感受器上还没有确定。TRPV1是一种在外周神经末梢表达的离子通道，负责检测产生疼痛的刺激，如热、酸和刺激性化学物质(如辣椒素，辣椒的热成分)。我们在这里展示了通道具有适应的基本属性，因为长时间的激活和通过通道的钙内流导致对进一步激活的敏感性显著降低，而不会降低通道的最大可能反应。为了解决这些机制，我们同时测量了通道反应性和质膜的一种成分PIP2，PIP2的耗竭可能是脱敏的基础。我们发现，PIP2的耗竭既有与电流脱敏同步的时间过程，又达到了足以显著改变通道反应性的程度，表明这一过程介导了TRPV1通道的适应。我们推测，适应是痛觉感受器的一个重要特征，可能有助于痛觉的可塑性。负责检测疼痛刺激的离子通道具有许多感官感受器中存在的对反应适应至关重要的特性。这意味着痛觉也能够在感受器水平上进行适应。
Adaptation is a common feature of many sensory systems. But its occurrence to pain sensation has remained elusive. Here we address the problem at the receptor level and show that the capsaicin ion channel TRPV1, which mediates nociception at the peripheral nerve terminals, possesses properties essential to the adaptation of sensory responses. Ca2+ influx following the channel opening caused a profound shift (∼14-fold) of the agonist sensitivity, but did not alter the maximum attainable current. The shift was adequate to render the channel irresponsive to normally saturating concentrations, leaving the notion that the channel became no longer functional after desensitization. By simultaneous patch-clamp recording and total internal reflection fluorescence (TIRF) imaging, it was shown that the depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) induced by Ca2+ influx had a rapid time course synchronous to the desensitization of the current. The extent of the depletion was comparable to that by rapamycin-induced activation of a PIP2 5-phosphatase, which also caused a significant reduction of the agonist sensitivity without affecting the maximum response. These results support a prominent contribution of PIP2 depletion to the desensitization of TRPV1 and suggest the adaptation as a possible physiological function for the Ca2+ influx through the channel. Sensory receptors can adjust their sensitivity to continuously varying stimuli, a process known as adaptation. Adaptation has been extensively studied in vision, hearing, and olfactory systems, but whether it also occurs to pain receptors has not been established. TRPV1 is an ion channel expressed in peripheral nerve terminals and is responsible for detection of pain-producing stimuli such as heat, acids, and irritant chemicals (e.g., capsaicin, the hot ingredient of chili peppers). We showed here that the channel has essential properties for adaptation since prolonged activation and calcium influx through the channel resulted in a dramatic decrease in sensitivity to further activation without reducing the maximal possible response of the channel. To address the mechanisms we simultaneously measured channel responsiveness and a component of the plasma membrane called PIP2 whose depletion may underlie desensitization. We showed that the depletion of PIP2 both had a time course synchronous to current desensitization and reached an extent adequate for significantly altering channel responsiveness, suggesting this process mediates the adaptation of TRPV1 channels. We postulate that adaptation is an important feature of pain receptors and may contribute to plasticity of pain sensation. Ion channels responsible for detection of painful stimuli have properties essential for the adaptation of responsiveness, as occurs in many sensory receptors. This implies that pain sensation is also capable of adaptation at the receptor level.
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