Endocannabinoid activation of the TRPV1 ion channel is distinct from activation by capsaicin.
Endocannabinoid activation of the TRPV1 ion channel is distinct from activation by capsaicin.
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内源性大麻素对TRPV1离子通道的激活与辣椒素的激活不同。
DOI：
10.1016/j.jbc.2021.101022
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Yang F
中科院分区：
文献类型：
--
作者：
Li Y;Chen X;Nie Y;Tian Y;Xiao X;Yang F
瞬时受体电位香草素1 （TRPV1）离子通道是42°C以上的有害温度、辣椒素等刺激性化学物质和酸性细胞外ph的探测器。该通道也被证明是一种嗜离子大麻素受体。尽管解决了TRPV1的高分辨率三维结构，但内源性大麻素（如anandamide和n -花生四烯酰基多巴胺）如何结合并激活该通道仍不得而知。在这里，我们采用膜片钳记录、定点诱变和分子对接技术相结合的方法来研究内源性大麻素如何在结构上结合并打开TRPV1离子通道。我们发现这些内源性大麻素配体以“尾朝上，头朝下”的结构与TRPV1的香草素结合袋结合，类似于辣椒素；然而，与TRPV1 Y512残基的独特相互作用对内源性大麻素激活TRPV1通道至关重要。这些数据表明，与经典的激动剂辣椒素相比，内源性大麻素激活TRPV1的结构机制存在差异。
Transient receptor potential vanilloid 1 (TRPV1) ion channel serves as the detector for noxious temperature above 42 °C, pungent chemicals like capsaicin, and acidic extracellular pH. This channel has also been shown to function as an ionotropic cannabinoid receptor. Despite the solving of high-resolution three-dimensional structures of TRPV1, how endocannabinoids such as anandamide and N-arachidonoyl dopamine bind to and activate this channel remains largely unknown. Here we employed a combination of patch-clamp recording, site-directed mutagenesis, and molecular docking techniques to investigate how the endocannabinoids structurally bind to and open the TRPV1 ion channel. We found that these endocannabinoid ligands bind to the vanilloid-binding pocket of TRPV1 in the “tail-up, head-down” configuration, similar to capsaicin; however, there is a unique interaction with TRPV1 Y512 residue critical for endocannabinoid activation of TRPV1 channels. These data suggest that a differential structural mechanism is involved in TRPV1 activation by endocannabinoids compared with the classic agonist capsaicin.
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DOI：
10.1007/978-1-61779-465-0_10
发表时间：
2012
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Lemmon, Gordon;Meiler, Jens
通讯作者：
Meiler, Jens
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影响因子：
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作者：
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通讯作者：
Hargreaves, Kenneth M.
影响因子：
5.6
作者：
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通讯作者：
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影响因子：
64.5
作者：
CARTER, PJ;WINTER, G;FERSHT, AR
通讯作者：
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DOI：
10.1016/b978-0-12-396493-9.00002-9
发表时间：
2012-01-01
期刊：
PROGRESS IN MEDICINAL CHEMISTRY, VOL 51
影响因子：
--
作者：
Kort, Michael E.;Kym, Philip R.
通讯作者：
Kym, Philip R.