Sulfide and polysulfide as pronociceptive mediators: Focus on Ca v 3.2 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 _v 3.2 T-type Ca ²⁺ channels by eliminating Zn ²⁺ bound to the channels, thereby promoting somatic and visceral pain. Ca _v 3.2 is under inhibition by Zn ²⁺ in physiological conditions, so that sulfides function to reboot Ca _v 3.2 from Zn ²⁺ 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 _v 3.2 function enhancement by sulfides and TRPA1 activation by polysulfides, synergistically accelerate somatic pain signals. The increased activity of the sulfide/Ca _v 3.2 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.
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