Discipline of Neuroscience and Department of Anatomy, Histology and Embryology, Collaborative Innovation Center for Brain Science, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX 77030, USA.
Cell Rep. 2015 Oct 13;13(2):387-98. doi: 10.1016/j.celrep.2015.09.002. Epub 2015 Oct 1.
The regulation and mechanisms underlying itch sensation are complex. Here, we report a role for acid-sensing ion channel 3 (ASIC3) in mediating itch evoked by certain pruritogens during tissue acidosis. Co-administration of acid with Ser-Leu-Ile-Gly-Arg-Leu-NH2 (SL-NH2) increased scratching behavior in wild-type, but not ASIC3-null, mice, implicating the channel in coincident detection of acidosis and pruritogens. Mechanistically, SL-NH2 slowed desensitization of proton-evoked currents by targeting the previously identified nonproton ligand-sensing domain located in the extracellular region of ASIC3 channels in primary sensory neurons. Ablation of the ASIC3 gene reduced dry-skin-induced scratching behavior and pathological changes under conditions with concomitant inflammation. Taken together, our data suggest that ASIC3 mediates itch sensation via coincident detection of acidosis and nonproton ligands that act at the nonproton ligand-sensing domain of the channel.
瘙痒感觉的调节和机制很复杂。在这里，我们报告酸感应离子通道 3（ASIC3）在介导某些瘙痒原在组织酸中毒时引起的瘙痒中的作用。在野生型小鼠中，酸与 Ser-Leu-Ile-Gly-Arg-Leu-NH2（SL-NH2）共同给药会增加抓挠行为，但在 ASIC3 敲除小鼠中不会，这表明该通道参与了酸中毒和瘙痒原的同时检测。从机制上讲，SL-NH2 通过靶向位于初级感觉神经元中 ASIC3 通道细胞外区域的先前鉴定的非质子配体感应结构域，减缓质子诱导电流的脱敏。ASIC3 基因的缺失减少了在伴有炎症的情况下干燥皮肤引起的抓挠行为和病理变化。总的来说，我们的数据表明，ASIC3 通过同时检测酸中毒和作用于通道的非质子配体感应结构域的非质子配体来介导瘙痒感觉。
