Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release.
Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release.
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DOI：
10.1371/journal.pone.0152405
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Stevens EB
中科院分区：
文献类型：
--
作者：
Alexandrou AJ;Brown AR;Chapman ML;Estacion M;Turner J;Mis MA;Wilbrey A;Payne EC;Gutteridge A;Cox PJ;Doyle R;Printzenhoff D;Lin Z;Marron BE;West C;Swain NA;Storer RI;Stupple PA;Castle NA;Hounshell JA;Rivara M;Randall A;Dib-Hajj SD;Krafte D;Waxman SG;Patel MK;Butt RP;Stevens EB
人类遗传学研究表明，电压门控钠通道1.7（Nav1.7）是痛觉的关键分子决定因素。然而，由于缺乏选择性抑制剂，确定Nav1.7对伤害性信号传导的贡献受到阻碍。在这里，我们报告了两个有效的和选择性的芳基磺酰胺Nav1.7抑制剂; PF-05198007和PF-05089771，我们已经用来直接询问Nav1.7在伤害感受器生理学中的作用。我们报告说，Nav1.7是小鼠和人类伤害感受器中的主要功能性TTX敏感性Navs，并有助于伤害感受器动作电位的起始和上行阶段。此外，我们证实了Nav1.7在影响脊髓背角的突触传递以及皮肤中的外周神经肽释放中的作用。这些发现表明Nav1.7对伤害感受器信号传导的多种贡献，并揭示了该通道对外周和中枢伤害信号传递的相对功能贡献。
Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining the Nav1.7 contribution to nociceptive signalling has been hampered by a lack of selective inhibitors. Here we report two potent and selective arylsulfonamide Nav1.7 inhibitors; PF-05198007 and PF-05089771, which we have used to directly interrogate Nav1.7’s role in nociceptor physiology. We report that Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors and contributes to the initiation and the upstroke phase of the nociceptor action potential. Moreover, we confirm a role for Nav1.7 in influencing synaptic transmission in the dorsal horn of the spinal cord as well as peripheral neuropeptide release in the skin. These findings demonstrate multiple contributions of Nav1.7 to nociceptor signalling and shed new light on the relative functional contribution of this channel to peripheral and central noxious signal transmission.