A Crucial Role for Hydrogen Sulfide in Oxygen Sensing via Modulating Large Conductance Calcium-Activated Potassium Channels

Abstract

Hydrogen sulfide (H(2)S) is an important signaling molecule produced from L-cysteine by cystathionine beta-synthetase (CBS) or cystathionine gamma-lyase (CSE). Here we examined the role of H(2)S in the oxygen-sensing function of the carotid body chemoreceptors, where the large conductance Ca(2+)-activated potassium channel (BK(Ca)) plays a key role. In the isolated mouse carotid body/sinus nerve preparations, the H(2)S donor, NaHS, excited the chemoreceptor afferent nerves in a concentration-dependent manner that was reversed by carbon monoxide donor. The NaHS-evoked excitation was abolished by removing extracellular Ca(2+), or using Cd(2+), pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid and hexomethonium, suggesting that H(2)S evokes release of ATP/ACh from type I glomus cells of the carotid body. The chemoreceptor afferent activation by hypoxia was decreased remarkably using CBS inhibitors, amino oxyacetic acid (AOAA) and hydroxylamine, but not CSE inhibitors, propargylglycine and beta-cyano-L-alanine, despite expression of both enzymes in type I glomus cells. In these cells, the BK(Ca) currents were inhibited by hypoxia and such inhibition was mimicked by NaHS and diminished by AOAA. Finally, mice hyperventilated in response to hypoxia, which was prevented by CBS inhibitors. These data suggest that H(2)S plays a crucial role in mediating the response of carotid body chemoreceptors to hypoxia via modulating the BK(Ca) channels.