Ca v 3.2 T‐type Ca 2+ Channels in H 2 S‐Mediated Hypoxic Response of the Carotid Body

Abstract

Voltage-gated Ca2+ channels (VGCC) are important for carotid body O2 sensing. We recently reported that Cav 3.2 is a major T-Type VGCC isoform expressed in the carotid body, and it contributes to hypoxia-evoked Ca2+ influx in glomus cells. Recent studies showed that cystathionine-γ-lyase (CSE)-derived hydrogen sulfide (H2S) is a critical mediator of carotid body response to hypoxia. We hypothesized that Cav 3.2-dependent carotid body response to hypoxia requires H2S. We tested this possibility in wild type (WT) and Cav 3.2 knockout (Cacna1h-/-) mice. In WT mice, NaHS, a H2S donor, like hypoxia, increased [Ca2+]i in glomus cells and carotid body sensory nerve activity, and these responses were markedly reduced in Cacna1h null glomus cells and carotid bodies. To assess the selective role of CSE-derived H2S, studies were performed on WT and CSE-/- mice. Hypoxia increased [Ca2+]i in glomus cells and this response was attenuated by TTA-A2, a selective blocker of T-type VGCC in WT but not in CSE null glomus cells. To determine whether genetic deletion of CSE impaired T-type VGCC function, CSE null glomus cells were challenged with NaHS. In response to NaHS, [Ca2+]i increased and this effect was inhibited by TTA-A2 in a reversible manner. Hypoxia-evoked carotid body sensory nerve excitation was reduced by TTA-A2 in WT, but not in CSE null carotid bodies. These results demonstrate that Cav 3.2 T-type VGCC contribute to H2S mediated carotid body response to hypoxia. Supported by NIH HL-90554.