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

Abstract

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 Scn11a 2/2 mice increased the hNa V 1.9 current density. By contrast, a PRMT7 inhibitor (DS-437) reduced mNa V 1.9 currents in Scn11a 1/1 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 1/1 mice but not Scn11a 2/2 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.

Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities

“… 1 , 2 Known substrates methylated by PRMT7 include core histones (H2A, H2B, H3, and H4), Wnt signaling molecules, and transcription factors, involving PRMT7 in a wide range of biological processes, such as gene expression and epigenetic regulation, cell differentiation, muscle and neuron development, and adipogenesis. 3 , 13 , 14 A significant number of genes involved in chromatin regulation have been associated with neurodevelopmental disorders, collectively known as chromatinopathies. 15 PRMT7- related disorder shares some overlapping phenotypes with chromatin-related neurodevelopmental disorders, particularly short stature and growth delay and presence of major craniofacial dysmorphisms and skeletal and digital abnormalities (eg, Wiedemann-Steiner syndrome and Chung-Jansen syndrome).…”

Epigenetic Mechanisms of Neural Plasticity in Chronic Neuropathic Pain

“…It is unclear what gene and protein targets are involved in PRMT4-induced arginine methylation of histone and non-histone proteins in neuropathic pain. In addition, PRMT7 interacts with Na V 1.9 ( Scn11a ) in the mouse DRG and methylates the arginine 519 (R519) residue in its hLoop1 . This increased methylation may facilitate the trafficking of Na V 1.9 to the cell membrane, augmenting neuronal excitability and nerve injury-induced neuropathic pain.…”

“…In addition, PRMT7 interacts with Na V 1.9 (Scn11a) in the mouse DRG and methylates the arginine 519 (R519) residue in its hLoop1. 52 This increased methylation may facilitate the trafficking of Na V 1.9 to the cell membrane, augmenting neuronal excitability and nerve injury-induced neuropathic pain.…”

PRMT7-Dependent Transcriptional Activation of Hmgb2 Aggravates Severe Acute Pancreatitis by Promoting Acsl1-Induced Ferroptosis

“…PRMT7 plays a significant role in promoting the progression of different types of malignancies, such as leukemia, melanoma, nonsmall-cell lung cancer, and breast cancer . Additionally, studies have reported that PRMT7 regulates neuronal excitability by modulating NaV1.9 currents and contributes to cardiac hypertrophy and fibrosis through dysregulation of β-catenin signaling pathway . Moreover, PRMT7 is involved in regulating oxidative metabolism processes as well. , However, the specific role played by PRMT7 in SAP remains unknown.…”