Physiological responses to hypoxia can be classified into immediate acute responses, occurring in seconds, and subacute to chronic responses, occurring over minutes to hours. Immediate acute responses are adaptive changes mediated mainly by O₂-regulated ion channels, which regulate the cell excitability, contractility, and secretory activity. Later responses depend on hypoxia-inducible transcription factors (HIFs) well known to be regulated through O₂-dependent protein metabolism: prolyl hydroxylation of HIF-1α by prolyl hydroxylases (PHDs) 1–3, which use molecular O₂ and 2-oxoglutarate as substrates. In contrast to the HIF-1α, the key mechanisms of acute O₂-sensing via ion channels remained elusive. An advance came with our discovery of TRPA1 sensing the O₂-availability including hypoxia and hyperoxia in peripheral sensory neurons. Recently, we have demonstrated that in astrocytes O₂ induces PHD hydroxylation coupled with NEDD4-1 ubiquitination that actively internalizes TRPA1 from the plasma membrane to inhibit the channel activity.  Under hypoxia, uncoupling of TRPA1 from this enhanced protein metabolism accumulates TRPA1 in the plasma membrane to mediate the Ca²⁺ influx responsible for ATP release in astrocytes, which potentiates the activity of the motor neurons critical for adaptive increases in breathing.  In this session, we address the question how ubiquitous the role played by TRPA1-mediated mechanism is through examination of carotid body glomus cells, the dogma of hypoxia sensing and adaptation, using Trpa1-deficient mice.