Mechanism of sodium channel Na^sub V^1.9 potentiation by G-protein signaling

• Published in: The Journal of general physiology Vol. 141; no. 2; p. 193
• Main Authors: Vanoye, Carlos G, Kunic, Jennifer D, Ehring, George R, George, Alfred L
• Format: Journal Article
• Language: English
• Published: New York Rockefeller University Press 01.02.2013
• Subjects: Cells; Glycoproteins; Neurons; Signal transduction; Sodium
• ISSN: 0022-1295; 1540-7748

Tetrodotoxin (TTX)-resistant voltage-gated Na (...) channels have been implicated in nociception. In particular, ... contributes to expression of persistent Na current in small diameter, nociceptive sensory neurons in dorsal root ganglia and is required for inflammatory pain sensation. Using ND7/23 cells stably expressing human ..., we elucidated the biophysical mechanisms responsible for potentiation of channel activity by G-protein signaling to better understand the response to inflammatory mediators. Heterologous ... expression evoked TTX-resistant Na current with peak activation at -40 mV with extensive overlap in voltage dependence of activation and inactivation. Inactivation kinetics were slow and incomplete, giving rise to large persistent Na currents. Single-channel recording demonstrated long openings and correspondingly high open probability (.) accounting for the large persistent current amplitude. Channels exposed to intracellular GTP...S, a proxy for G-protein signaling, exhibited twofold greater current density, slowing of inactivation, and a depolarizing shift in voltage dependence of inactivation but no change in activation voltage dependence. At the single-channel level, intracellular GTP...S had no effect on single-channel amplitude but caused an increased mean open time and greater Po compared with recordings made in the absence of GTP...S. We conclude that G-protein activation potentiates human ... activity by increasing channel open probability and mean open time, causing the larger peak and persistent current, respectively. Our results advance our understanding about the mechanism of ... potentiation by G-protein signaling during inflammation and provide a cellular platform useful for the discovery of NaV1.9 modulators with potential utility in treating inflammatory pain. (ProQuest: ... denotes formulae/symbols omitted.)