Hydrogen Sulfide as an Oxygen Sensor

Significance: Although oxygen (O-2)-sensing cells and tissues have been known for decades, the identity of the O-2-sensing mechanism has remained elusive. Evidence is accumulating that O-2-dependent metabolism of hydrogen sulfide (H2S) is this enigmatic O-2 sensor. Recent Advances: The elucidation of biochemical pathways involved in H2S synthesis and metabolism have shown that reciprocal H2S/O-2 interactions have been inexorably linked throughout eukaryotic evolution; there are multiple foci by which O-2 controls H2S inactivation, and the effects of H2S on downstream signaling events are consistent with those activated by hypoxia. H2S-mediated O-2 sensing has been demonstrated in a variety of O-2-sensing tissues in vertebrate cardiovascular and respiratory systems, including smooth muscle in systemic and respiratory blood vessels and airways, carotid body, adrenal medulla, and other peripheral as well as central chemoreceptors. Critical Issues: Information is now needed on the intracellular location and stoichometry of these signaling processes and how and which downstream effectors are activated by H2S and its metabolites. Future Directions: Development of specific inhibitors of H2S metabolism and effector activation as well as cellular organelle-targeted compounds that release H2S in a time- or environmentally controlled way will not only enhance our understanding of this signaling process but also provide direction for future therapeutic applications. Antioxid. Redox Signal. 22, 377-397. "Nothing in Biology Makes Sense Except in the Light of Evolution" -Theodosius Dobzhansky (29)