Activation of TRPM3 by a potent synthetic ligand reveals a role in peptide release
Activation of TRPM3 by a potent synthetic ligand reveals a role in peptide release
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DOI：
10.1073/pnas.1419845112
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发表时间：
2015-03-17
影响因子：
11.1
通讯作者：
Vriens, Joris
中科院分区：
文献类型：
--
作者：
Held, Katharina;Kichko, Tatjana;Vriens, Joris
瞬时受体电位（TRP）阳离子通道亚家族M成员3（TRPM 3），TRP通道超家族的成员，最近被确定为体感系统中的伤害感受器通道，在那里它参与检测有害热;然而，由于缺乏有效的和选择性的激动剂，很少有人知道TRPM 3开放的其他潜在生理后果。在这里，我们确定并表征了一种合成的TRPM 3激活剂，CIM 0216，其效力和表观亲和力大大超过了经典的TRPM 3激动剂，硫酸双烯醇酮（PS）。特别是，单次施用CIM 0216会以膜界定的方式打开中央钙传导孔和替代阳离子渗透途径。CIM 0216在表达TRPM 3的体感神经元中诱发了强烈的钙内流，并且皮内注射该化合物诱导了TRPM 3依赖性疼痛反应行为。此外，CIM 0216以TRPM 3依赖性方式引起降钙素基因相关肽（CGRP）从感觉神经末梢和胰岛素从分离的胰岛的释放。这些实验将CIM 0216鉴定为用于研究TRPM 3的生理作用的有力工具，并表明感觉神经末梢中的TRPM 3活化可促成神经源性炎症。
Transient receptor potential (TRP) cation channel subfamily M member 3 (TRPM3), a member of the TRP channel superfamily, was recently identified as a nociceptor channel in the somatosensory system, where it is involved in the detection of noxious heat; however, owing to the lack of potent and selective agonists, little is known about other potential physiological consequences of the opening of TRPM3. Here we identify and characterize a synthetic TRPM3 activator, CIM0216, whose potency and apparent affinity greatly exceeds that of the canonical TRPM3 agonist, pregnenolone sulfate (PS). In particular, a single application of CIM0216 causes opening of both the central calcium-conducting pore and the alternative cation permeation pathway in a membrane-delimited manner. CIM0216 evoked robust calcium influx in TRPM3-expressing somatosensory neurons, and intradermal injection of the compound induced a TRPM3-dependent nocifensive behavior. Moreover, CIM0216 elicited the release of the peptides calcitonin generelated peptide (CGRP) from sensory nerve terminals and insulin from isolated pancreatic islets in a TRPM3-dependent manner. These experiments identify CIM0216 as a powerful tool for use in investigating the physiological roles of TRPM3, and indicate that TRPM3 activation in sensory nerve endings can contribute to neurogenic inflammation.