Sulfide and polysulfide as pronociceptive mediators: Focus on Ca_v3.2 function enhancement and TRPA1 activation

Reactive sulfur species including sulfides, polysulfides and cysteine hydropersulfide play extensive roles in health and disease, which involve modification of protein functions through the interaction with metals bound to the proteins, cleavage of cysteine disulfide (S-S) bonds and S-persulfidation of cysteine residues. Sulfides over a wide micromolar concentration range enhance the activity of Ca_v3.2 T-type Ca²⁺ channels by eliminating Zn²⁺ bound to the channels, thereby promoting somatic and visceral pain. Ca_v3.2 is under inhibition by Zn²⁺ in physiological conditions, so that sulfides function to reboot Ca_v3.2 from Zn²⁺ inhibition and increase the excitability of nociceptors. On the other hand, polysulfides generated from sulfides activate TRPA1 channels via cysteine S-persulfidation, thereby facilitating somatic, but not visceral, pain. Thus, Ca_v3.2 function enhancement by sulfides and TRPA1 activation by polysulfides, synergistically accelerate somatic pain signals. The increased activity of the sulfide/Ca_v3.2 system, in particular, appears to have a great impact on pathological pain, and may thus serve as a therapeutic target for treatment of neuropathic and inflammatory pain including visceral pain.