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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Direct interaction of adenosine with the TRPV1 channel protein.
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Direct interaction of adenosine with the TRPV1 channel protein.

机译：腺苷与TRPV1通道蛋白的直接相互作用。

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摘要

Vanilloid receptor 1 (TRPV1), a nonspecific cation channel expressed primarily in small sensory neurons, mediates inflammatory thermal pain sensation. The function and expression of TRPV1 are enhanced during inflammation and certain neuropathies, leading to sustained hyperalgesia. Activation of TRPV1 in the spinal cord and periphery promotes release of adenosine, which produces analgesia by activating A(1) and A(2A) adenosine receptor (AR) on central and peripheral neurons. This study provides evidence of a direct interaction of AR analogs with TRPV1. Adenosine analogs inhibit TRPV1-mediated Ca(2+) entry in human embryonic kidney (HEK293) cells stably expressing TRPV1 (HEK/TRPV1) and DRG neurons. This inhibition was independent of A(2A)AR activation. Specific binding of [(3)H]resiniferatoxin (RTX) in plasma membrane preparations was inhibited by CGS21680, an A(2A)AR agonist. Similar degrees of inhibition were observed with both agonists and antagonists of ARs. Adenosine analogs inhibited [(3)H]RTX binding to affinity-purified TRPV1, indicative of a direct interaction of these ligands with the receptor. Furthermore, specific capsaicin-sensitive binding of [(3)H]CGS21680 was observed in Xenopus oocyte membranes expressing TRPV1. Capsaicin-induced inward currents in DRG neurons were inhibited by adenosine and agonist and antagonist of A(2A)AR at nanomolar concentrations. Increasing the concentrations of capsaicin reversed the inhibitory response to capsaicin, suggesting a competitive inhibition at TRPV1. Finally, exposure of HEK/TRPV1 cells to capsaicin induced an approximately 2.4-fold increase in proapoptotic cells that was abolished by adenosine analogs. Together, these data suggest that adenosine could serve as an endogenous inhibitor of TRPV1 activity by directly interacting with the receptor protein.
机译：Vanilloid受体1（TRPV1），主要在小感觉神经元中表达的非特异性阳离子通道，介导炎性热痛感。在炎症和某些神经病期间，TRPV1的功能和表达增强，导致持续的痛觉过敏。脊髓和外周中TRPV1的激活促进腺苷的释放，通过激活中央和周围神经元上的A（1）和A（2A）腺苷受体（AR）来产生镇痛作用。这项研究提供了AR类似物与TRPV1直接相互作用的证据。腺苷类似物抑制TRPV1介导的Ca（2+）进入稳定表达TRPV1（HEK / TRPV1）和DRG神经元的人胚胎肾脏（HEK293）细胞。此抑制独立于A（2A）AR激活。 A（2A）AR激动剂CGS21680抑制质膜制剂中[（3）H]树脂毒素（RTX）的特异性结合。用ARs的激动剂和拮抗剂观察到相似的抑制程度。腺苷类似物抑制[（3）H] RTX与亲和纯化的TRPV1的结合，表明这些配体与受体的直接相互作用。此外，在表达TRPV1的非洲爪蟾卵母细胞膜中观察到[（3）H] CGS21680的辣椒素特异性结合。辣椒素诱导的DRG神经元内向电流被腺苷，纳摩尔浓度的激动剂和A（2A）AR拮抗剂抑制。辣椒素浓度的增加会逆转对辣椒素的抑制反应，表明对TRPV1有竞争性抑制作用。最后，将HEK / TRPV1细胞暴露于辣椒素会诱导促凋亡细胞增加约2.4倍，而腺苷类似物可将其消除。总之，这些数据表明腺苷可通过与受体蛋白直接相互作用而成为TRPV1活性的内源性抑制剂。

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