Reducing agents sensitize C-type nociceptors by relieving high-affinity zinc inhibition of T-type calcium channels.
Recent studies have demonstrated an important role for T-type Ca2+ channels (T-channels) in controlling the excitability of peripheral pain-sensing neurons (nociceptors). However, the molecular mechanisms underlying the functions of T-channels in nociceptors are poorly understood. Here, we demonstrate that reducing agents as well as endogenous metal chelators sensitize C-type dorsal root ganglion nociceptors by chelating Zn2+ ions off specific extracellular histidine residues on Ca(v)3.2 T-channels, thus relieving tonic channel inhibition, enhancing Ca(v)3.2 currents, and lowering the threshold for nociceptor excitability in vitro and in vivo. Collectively, these findings describe a novel mechanism of nociceptor sensitization and firmly establish reducing agents, as well as Zn2+, Zn2+-chelating amino acids, and Zn2+-chelating proteins as endogenous modulators of Ca(v)3.2 and nociceptor excitability.
Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
Michael T
MT
Nelson
Jiwan
J
Woo
Ho-Won
HW
Kang
Iuliia
I
Vitko
Paula Q
PQ
Barrett
Edward
E
Perez-Reyes
Jung-Ha
JH
Lee
Hee-Sup
HS
Shin
Slobodan M
SM
Todorovic
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009619:Nociceptors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019163:Reducing Agents / Q000494:pharmacology*; D015032:Zinc / Q000494:pharmacology*
C504883:Cacna1h protein, mouse; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D019163:Reducing Agents; D015032:Zinc