Magi-1 scaffolds NaV1.8 and Slack KNa channels in dorsal root ganglion neurons regulating excitability and pain

Voltage-dependent sodium (NaV) 1.8 channels regulate action potential generation in nociceptive neurons, identifying them as putative analgesic targets. Here, we show that NaV1.8 channel plasma membrane localization, retention, and stability occur through a direct interaction with the postsynaptic density-95/discs large/zonula occludens-1–and WW domain–containing scaffold protein called membrane-associated guanylate kinase with inverted orientation (Magi)-1. The neurophysiological roles of Magi-1 are largely unknown, but we found that dorsal root ganglion (DRG)–specific knockdown of Magi-1 attenuated thermal nociception and acute inflammatory pain and produced deficits in NaV1.8 protein expression. A competing cell-penetrating peptide mimetic derived from the NaV1.8 WW binding motif decreased sodium currents, reduced NaV1.8 protein expression, and produced hypoexcitability. Remarkably, a phosphorylated variant of the very same peptide caused an opposing increase in NaV1.8 surface expression and repetitive...