TRPV1 channels are intrinsically heat sensitive and negatively regulated by phosphoinositide lipids.
TRPV1 channels are intrinsically heat sensitive and negatively regulated by phosphoinositide lipids.
复制标题
DOI：
10.1016/j.neuron.2012.12.016
复制
发表时间：
2013-02-20
期刊：
影响因子：
16.2
通讯作者：
Julius D
中科院分区：
文献类型：
--
作者：
Cao E;Cordero-Morales JF;Liu B;Qin F;Julius D
辣椒素受体TRPV 1受磷脂酰肌醇-4，5-二磷酸（PIP 2）调节，尽管这种作用的确切性质（即，积极的或消极的，仍有争议。在这里，我们将纯化的TRPV 1重组到人工脂质体中，在那里它被辣椒素，质子，蜘蛛毒素和特别是热有力地门控，证明了通道对化学和热刺激的内在敏感性。TRPV 1是完全功能的磷酸肌醇的情况下，反对他们提出的通道激活的强制性作用。相反，引入各种磷酸肌醇，包括PIP 2，PI 4P和PI，抑制TRPV 1，支持磷酸肌醇周转通过解除通道抑制而导致热痛觉过敏的模型。使用正交的化学策略，我们表明，TRPV 1的C-末端与双层协会调制通道门控，与系统发育数据暗示这一领域作为一个关键的调控位点调谐刺激敏感性一致。除了TRPV 1，这些发现与了解膜脂如何调节其他“受体操作”的TRP通道有关。
The capsaicin receptor, TRPV1, is regulated by phosphatidylinositol-4,5-bisphosphate (PIP2), although the precise nature of this effect (i.e., positive or negative) remains controversial. Here, we reconstitute purified TRPV1 into artificial liposomes, where it is gated robustly by capsaicin, protons, spider toxins and, notably, heat, demonstrating intrinsic sensitivity of the channel to both chemical and thermal stimuli. TRPV1 is fully functional in the absence of phosphoinositides, arguing against their proposed obligatory role in channel activation. Rather, introduction of various phosphoinositides, including PIP2, PI4P and PI, inhibits TRPV1, supporting a model whereby phosphoinositide turnover contributes to thermal hyperalgesia by disinhibiting the channel. Using an orthogonal chemical strategy, we show that association of the TRPV1 C-terminus with the bilayer modulates channel gating, consistent with phylogenetic data implicating this domain as a key regulatory site for tuning stimulus sensitivity. Beyond TRPV1, these findings are relevant to understanding how membrane lipids modulate other “receptor-operated” TRP channels.
登录
查看更多内容
影响因子：
64.8
作者：
Hansen, Scott B.;Tao, Xiao;MacKinnon, Roderick
通讯作者：
MacKinnon, Roderick
影响因子：
64.8
作者：
Chuang, HH;Prescott, ED;Julius, D
通讯作者：
Julius, D
影响因子：
4.8
作者：
Hardie, RC;Gu, YC;Raghu, P
通讯作者：
Raghu, P
影响因子：
64.8
作者：
Gracheva, Elena O.;Cordero-Morales, Julio F.;Gonzalez-Carcacia, Jose A.;Ingolia, Nicholas T.;Manno, Carlo;Aranguren, Carla I.;Weissman, Jonathan S.;Julius, David
通讯作者：
Julius, David
影响因子：
64.5
作者：
Jordt, SE;Julius, D
通讯作者：
Julius, D