Roles of the Hydrogen Sulfide/T- Type Calcium Channel System in Somatic and Visceral Pain Processing

Hydrogen sulfide (H2S), a gasotransmitter, is endogenously formed from Lcysteine by certain enzymes including cystathionineγlyase (CSE) in the mammalian body. H2S sensitizes Cav3.2 Ttype calcium channels, leading to excitation of sensory neurons followed by somatic hyperalgesia in rats and mice. The enhanced activity of the H2S/Cav3.2 system is involved in the neuropathic pain/hyperalgesia induced by repeated administration of paclitaxel, an anticancer drug, or by spinal nerve injury. It is also noteworthy that the H2Sinduced mechanical hyperalgesia requires activation of both Cav3.2 and transient receptor potential A1 (TRPA1) channels in mice. H2S and Cav3.2 Ttype calcium channels are also involved in processing of visceral nociception including colonic, pancreatic and bladder pain. Endogenous H2S formed by upregulated CSE contributes to the pancreatitisrelated pain. Further, the excitation of sensory nerves by H2S through Ttype calcium channels exerts mucosal cytoprotection against colitis in rats. Together, endogenous H2S formed by CSE appears to stimulate sensory nerves by targeting Cav3.2 Ttype calcium channels and, in some cases, TRPA1 channels, leading to facilitation of somatic and visceral pain signals and also contributing to colonic mucosal cytoprotection. Thus, the CSE/H2S/Cav3.2 system may serve as therapeutic targets for treatment of neuropathic or visceral pain and of colitis. Copyright © 2012 S. Karger AG, Basel Hydrogen sulfide (H2S) is now considered the third gasotransmitter after nitric oxide (NO) and carbon monoxide (CO), and plays a variety of roles in health and disease. H2S is formed from lcysteine through three distinct enzymatic pathways catalyzed by cystathionineγlyase (CSE), cystathionineβsynthase (CBS) and 3mercaptopyruvate sulfurtransferase (MST) along with cysteine aminotransferase (CAT) [1] (fig. 1). Like NO and CO, H2S is a highly lipophilic molecule able to freely penetrate the cell membrane [2], and targets multiple molecules including Cav3.2 Ttype calcium channels [3, 4], transient receptor potential A1 (TRPA1) channels [5] and ATPsensitive potassium (KATP) channels [6] in the mammalian body [7]. Some