Inhibition of T-type Ca2+ Channels by Hydrogen Sulfide
- 2.2k Downloads
T-type Ca2+ channels are a distinct family of low voltage-activated Ca2+ 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 (H2S) was more recently discovered as an important signalling molecule involved in many functions, including O2 sensing. Since ion channels are emerging as an important family of target proteins for modulation by H2S, and both T-type Ca2+ channels and H2S are involved in cellular responses to hypoxia, we have investigated whether recombinant and native T-type Ca2+ channels are a target for modulation by H2S. Using patch-clamp electrophysiology, we demonstrate that the H2S donor, NaHS, selectively inhibits Cav3.2 T-type Ca2+ 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 Zn2+ to this channel. Chelation of Zn2+ using TPEN prevented channel inhibition by H2S. H2S also selectively inhibited native T-type channels (primarily Cav3.2) in sensory dorsal root ganglion neurons. Our data demonstrate a novel target for H2S regulation, the T-type Ca2+ 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.
KeywordsHydrogen sulfide T-type Ca2+ channel HEK293 cells Sensory neuron Zinc Patch clamp
This work was supported by The British Heart Foundation.
- Nelson MT, Joksovic PM, Su P, Kang HW, Van DA, Baumgart JP, David LS, Snutch TP, Barrett PQ, Lee JH, Zorumski CF, Perez-Reyes E, Todorovic SM (2007a) Molecular mechanisms of subtype-specific inhibition of neuronal T-type calcium channels by ascorbate. J Neurosci 27:12577–12583PubMedCrossRefGoogle Scholar
- Papapetropoulos A, Whiteman M, Giuseppe C (2015) Pharmacological tools for hydrogen sulfide research: a brief, introductory guide for beginners. Br J Pharmacol 172(6):1633–1637Google Scholar
- Wan J, Yamamura A, Zimnicka AM, Voiriot G, Smith KA, Tang H, Ayon RJ, Choudhury MS, Ko EA, Wang J, Wang C, Makino A, Yuan JX (2013) Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca2+ channel activity in pulmonary artery by upregulating Cav1.2 and Cav3.2. Am J Physiol Lung Cell Mol Physiol 305:L154–L164PubMedCrossRefPubMedCentralGoogle Scholar