Protein arginine methyltransferase 7 modulates neuronal excitability by interacting with Na_v1.9

Human Na(v)1.9 (hNa(v)1.9), encoded by SCN11A, is preferentially expressed in nociceptors, and its mutations have been linked to pain disorders. Na(v)1.9 could be a promising drug target for pain relief. However, the modulation of Na(v)1.9 activity has remained elusive. Here, we identified a new candidate Na(v)1.9-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 Scn11(-/-) mice increased the hNa(v)1.9 current density. By contrast, a PRMT7 inhibitor (DS-437) reduced mNa(v)1.9 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 hNa(v)1.9 (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 Scn11a(A796G/A796G) mice. In summary, our observations revealed that PRMT7 modulates neuronal excitability by regulating Na(v)1.9 currents, which may provide a potential method for pain treatment.