title: Inhibition of T-type Ca2+ Channels by Hydrogen Sulfide.
abstract: T-type Ca(2+) channels are a distinct family of low voltage-activated Ca(2+) channels which serve many roles in different tissues. Several studies have implicated them, for example, in the adaptive responses to chronic hypoxia in the cardiovascular and endocrine systems. Hydrogen sulfide (H(2)S) was more recently discovered as an important signalling molecule involved in many functions, including O(2) sensing. Since ion channels are emerging as an important family of target proteins for modulation by H(2)S, and both T-type Ca(2+) channels and H(2)S are involved in cellular responses to hypoxia, we have investigated whether recombinant and native T-type Ca(2+) channels are a target for modulation by H(2)S. Using patch-clamp electrophysiology, we demonstrate that the H(2)S donor, NaHS, selectively inhibits Cav3.2 T-type Ca(2+) channels heterologously expressed in HEK293 cells, whilst Cav3.1 and Cav3.3 channels were unaffected. 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+) using TPEN prevented channel inhibition by H(2)S. H2S also selectively inhibited native T-type channels (primarily Cav3.2) in sensory dorsal root ganglion neurons. Our data demonstrate a novel target for H(2)S regulation, the T-type Ca(2+) channel Cav3.2. Results have important implications for the proposed pro-nociceptive effects of this gasotransmitter. Implications for the control of cellular responses to hypoxia await further study.
authors: Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK.
authors: Jacobo
authors: J
authors: Elies
authors: Jason L
authors: JL
authors: Scragg
authors: Mark L
authors: ML
authors: Dallas
authors: Dongyang
authors: D
authors: Huang
authors: Sha
authors: S
authors: Huang
authors: John P
authors: JP
authors: Boyle
authors: Nikita
authors: N
authors: Gamper
authors: Chris
authors: C
authors: Peers
mesh_terms: D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D005029:Ethylenediamines / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*
chemical_list: C479952:CACNA1H protein, human; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D005029:Ethylenediamines; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine; D006862:Hydrogen Sulfide