Magi-1 scaffolds Na_V1.8 and Slack K_Nachannels in dorsal root ganglion neurons regulating excitability and pain

Voltage-dependent sodium (Na_V) 1.8 channels regulate action potential generation in nociceptive neurons, identifying them as putative analgesic targets. Here, we show that Na_V1.8 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 Na_V1.8 protein expression. A competing cell-penetrating peptide mimetic derived from the Na_V1.8 WW binding motif decreased sodium currents, reduced Na_V1.8 protein expression, and produced hypoexcitability. Remarkably, a phosphorylated variant of the very same peptide caused an opposing increase in Na_V1.8 surface expression and repetitive firing. Likewise, in vivo, the peptides produced diverging effects on nocifensive behavior. Additionally, we found that Magi-1 bound to sequence like a calcium-activated potassium channel sodium-activated (Slack) potassium channels, demonstrating macrocomplexing with Na_V1.8 channels. Taken together, these findings emphasize Magi-1 as an essential scaffold for ion transport in DRG neurons and a central player in pain.—Pryce, K. D., Powell, R., Agwa, D., Evely, K. M., Sheehan, G. D., Nip, A., Tomasello, D. L., Gururaj, S., Bhattacharjee, A. Magi-1 scaffolds Na_V1.8 and Slack K_Na channels in dorsal root ganglion neurons regulating excitability and pain.