Details

Autor(en) / Beteiligte

• Pryce, Kerri D
• Powell, Rasheen
• Agwa, Dalia
• Evely, Katherine M
• Sheehan, Garrett D
• Nip, Allan
• Tomasello, Danielle L
• Gururaj, Sushmitha
• Bhattacharjee, Arin

Titel

Magi-1 scaffolds Na V 1.8 and Slack K Na channels in dorsal root ganglion neurons regulating excitability and pain

Ist Teil von

• The FASEB journal, 2019-06, Vol.33 (6), p.7315

Ort / Verlag

United States

Erscheinungsjahr

2019

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• Voltage-dependent sodium (Na ) 1.8 channels regulate action potential generation in nociceptive neurons, identifying them as putative analgesic targets. Here, we show that Na 1.8 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 1.8 protein expression. A competing cell-penetrating peptide mimetic derived from the Na 1.8 WW binding motif decreased sodium currents, reduced Na 1.8 protein expression, and produced hypoexcitability. Remarkably, a phosphorylated variant of the very same peptide caused an opposing increase in Na 1.8 surface expression and repetitive firing. Likewise, , 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 1.8 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 1.8 and Slack K channels in dorsal root ganglion neurons regulating excitability and pain.