Oxygen Sensing by the Carotid Body: Is It All Just Rotten Eggs?

Abstract

Significance: Ventilatory responses to hypoxia are initiated by the carotid body, where inhibition of specific K⁺ channels causes cell depolarization, voltage-gated Ca²⁺ influx, and neurotransmitter release. The identity of the upstream oxygen (O₂) sensor is still controversial. Recent Advances: The activity of BK_Ca channels is regulated by O₂, carbon monoxide (CO), and hydrogen sulfide (H₂S), suggesting that integration of these signals may be crucial to the physiological response of this tissue. BK_Ca is colocalized with hemeoxygenase-2, an enzyme that generates CO in the presence of O₂, and CO is a BK_Ca channel opener. Reduced CO during hypoxia results in channel closure, conferring a degree of O₂ sensitivity to the BK_Ca channel. Conversely, H₂S is a potent BK_Ca inhibitor. H₂S is produced endogenously by cystathionine-β-synthase and cystathionine-γ-lyase in the rat carotid body, and its intracellular concentration is dependent upon the balance between its enzymatic generation and its mitochondrial breakdown. During hypoxia, mitochondrial oxidation of H₂S in many tissues is reduced, leading to hypoxia-evoked rises in its concentration. This may be sufficient to inhibit K⁺ channels and lead to carotid body excitation. Critical Issues: Carotid body function is heavily dependent upon regulated production and breakdown of CO and H₂S and integration of signals from these newly emerging gasotransmitters, in combination with several other proposed mechanisms, may refine, or even define, responses of this tissue to hypoxia. Future Directions: Since several other sensors have been postulated, the challenge of future research is to begin to integrate each in a unifying mechanism, as has been attempted for the first time herein. Antioxid. Redox Signal. 20, 794–804.