Protein arginine methyltransferase 7 modulates neuronal excitability by interacting with NaV1.9.

Human NaV1.9 (hNaV1.9), encoded by SCN11A, is preferentially expressed in nociceptors, and its mutations have been linked to pain disorders. NaV1.9 could be a promising drug target for pain relief. However, the modulation of NaV1.9 activity has remained elusive. Here, we identified a new candidate NaV1.9-interacting partner, protein arginine methyltransferase 7 (PRMT7). Whole-cell voltage-clamp recordings showed that coelectroporation of human SCN11A and PRMT7 in dorsal root ganglion (DRG) neurons of Scn11a-/- mice increased the hNaV1.9 current density. By contrast, a PRMT7 inhibitor (DS-437) reduced mNaV1.9 currents in Scn11a+/+ mice. Using the reporter molecule CD4, we observed an increased distribution of hLoop1 on the cell surface of PRMT7-overexpressing HKE293T cells. Furthermore, we found that PRMT7 mainly binds to residues 563 to 566 within the first intracellular loop of hNaV1.9 (hLoop1) and methylates hLoop1 at arginine residue 519. Moreover, overexpression of PRMT7 increased the number of action potential fired in DRG neurons of Scn11a+/+ mice but not Scn11a-/- mice. However, DS-437 significantly inhibited the action potential frequency of DRG neurons and relieved pain hypersensitivity in Scn11aA796G/A796G mice. In summary, our observations revealed that PRMT7 modulates neuronal excitability by regulating NaV1.9 currents, which may provide a potential method for pain treatment. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.

Citation

Tingbin Ma, Lulu Li, Rui Chen, Luyao Yang, Hao Sun, Shiyue Du, Xuan Xu, Zhijian Cao, Xianwei Zhang, Luoying Zhang, Xiaoliu Shi, Jing Yu Liu. Protein arginine methyltransferase 7 modulates neuronal excitability by interacting with NaV1.9. Pain. 2022 Apr 01;163(4):753-764

Mesh Tags

Substances

PMID: 34326297

search → result