title: Hydrogen sulfide inhibits Cav3.2 T-type Ca2+ channels.
abstract: The importance of H2S as a physiological signaling molecule continues to develop, and ion channels are emerging as a major family of target proteins through which H2S exerts many actions. The purpose of the present study was to investigate its effects on T-type Ca(2+) channels. Using patch-clamp electrophysiology, we demonstrate that the H2S donor, NaHS (10 μM-1 mM) selectively inhibits Cav3.2 T-type channels heterologously expressed in HEK293 cells, whereas Cav3.1 and Cav3.3 channels were unaffected. The sensitivity of Cav3.2 channels to H2S required the presence of the redox-sensitive extracellular residue H191, which is also required for tonic binding of Zn(2+) to this channel. Chelation of Zn(2+) with N,N,N',N'-tetra-2-picolylethylenediamine prevented channel inhibition by H2S and also reversed H2S inhibition when applied after H2S exposure, suggesting that H2S may act via increasing the affinity of the channel for extracellular Zn(2+) binding. Inhibition of native T-type channels in 3 cell lines correlated with expression of Cav3.2 and not Cav3.1 channels. Notably, H2S also inhibited native T-type (primarily Cav3.2) channels in sensory dorsal root ganglion neurons. Our data demonstrate a novel target for H2S regulation, the T-type Ca(2+) channel Cav3.2, and suggest that such modulation cannot account for the pronociceptive effects of this gasotransmitter.
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, and.
authors.forename: Jacobo
authors.initials: J
authors.lastname: Elies
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, and.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Scragg
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, China; and.
authors.forename: Sha
authors.initials: S
authors.lastname: Huang
authors.affiliation: School of Pharmacy, University of Reading, Reading, UK.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Dallas
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, China; and.
authors.forename: Dongyang
authors.initials: D
authors.lastname: Huang
authors.affiliation: School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, UK;
authors.forename: David
authors.initials: D
authors.lastname: MacDougall
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, and.
authors.forename: John P
authors.initials: JP
authors.lastname: Boyle
authors.affiliation: School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, UK; Department of Pharmacology, Hebei Medical University, Shijiazhuang, China; and.
authors.forename: Nikita
authors.initials: N
authors.lastname: Gamper
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, and c.s.peers@leeds.ac.uk.
authors.forename: Chris
authors.initials: C
authors.lastname: Peers
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C479952:CACNA1H protein, human; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D006862:Hydrogen Sulfide