Jiang Yan, Castro Joel, Blomster Linda V, Agwa Akello J, Maddern Jessica, Schober Gudrun, Herzig Volker, Chow Chun Yuen, Cardoso Fernanda C, Demétrio De Souza França Paula, Gonzales Junior, Schroeder Christina I, Esche Steffen, Reiner Thomas, Brierley Stuart M, King Glenn F
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, Bedford Park, South Australia 5042, Australia.
ACS Pharmacol Transl Sci. 2021 Jun 7;4(4):1362-1378. doi: 10.1021/acsptsci.1c00072. eCollection 2021 Aug 13.
The human nociceptor-specific voltage-gated sodium channel 1.7 (hNa1.7) is critical for sensing various types of somatic pain, but it appears not to play a primary role in acute visceral pain. However, its role in chronic visceral pain remains to be determined. We used assay-guided fractionation to isolate a novel hNa1.7 inhibitor, Tsp1a, from tarantula venom. Tsp1a is 28-residue peptide that potently inhibits hNa1.7 (IC = 10 nM), with greater than 100-fold selectivity over hNa1.3-hNa1.6, 45-fold selectivity over hNa1.1, and 24-fold selectivity over hNa1.2. Tsp1a is a gating modifier that inhibits Na1.7 by inducing a hyperpolarizing shift in the voltage-dependence of channel inactivation and slowing recovery from fast inactivation. NMR studies revealed that Tsp1a adopts a classical knottin fold, and like many knottin peptides, it is exceptionally stable in human serum. Remarkably, intracolonic administration of Tsp1a completely reversed chronic visceral hypersensitivity in a mouse model of irritable bowel syndrome. The ability of Tsp1a to reduce visceral hypersensitivity in a model of irritable bowel syndrome suggests that pharmacological inhibition of hNa1.7 at peripheral sensory nerve endings might be a viable approach for eliciting analgesia in patients suffering from chronic visceral pain.
人类伤害感受器特异性电压门控钠通道1.7（hNa1.7）对于感知各种类型的躯体疼痛至关重要，但它似乎在急性内脏疼痛中不发挥主要作用。然而，其在慢性内脏疼痛中的作用仍有待确定。我们采用分析引导分级分离法从狼蛛毒液中分离出一种新型hNa1.7抑制剂Tsp1a。Tsp1a是一种由28个氨基酸残基组成的肽，能有效抑制hNa1.7（IC = 10 nM），对hNa1.3 - hNa1.6的选择性大于100倍，对hNa1.1的选择性为45倍，对hNa1.2的选择性为24倍。Tsp1a是一种门控修饰剂，通过诱导通道失活电压依赖性的超极化偏移并减缓从快速失活中的恢复来抑制Na1.7。核磁共振研究表明，Tsp1a具有经典的结蛋白折叠结构，并且与许多结蛋白肽一样，它在人血清中异常稳定。值得注意的是，在肠易激综合征小鼠模型中，结肠内给予Tsp1a可完全逆转慢性内脏超敏反应。Tsp1a在肠易激综合征模型中降低内脏超敏反应的能力表明，在外周感觉神经末梢对hNa1.7进行药理学抑制可能是为患有慢性内脏疼痛的患者产生镇痛作用的一种可行方法。
