We previously showed that activation of Olfr78 by H 2 S as an important component of carotid body(CB) O 2 sensing. Present study delineated signaling associated with H 2 S/Olfr78 interaction. Odorant receptor activation is linked to olfactory G protein G Olf , which increases cAMP through type III adenylyl cyclase (AC3), and subsequent activation of cyclic nucleotide-gated channel alpha 2 (Cnga2). Immunohistochemistry showed that carotid body glomus cells were positive for Gα Olf , AC3, and Cnga2. Hypoxia (medium Po 2 ~40 mmHg) or H 2 S(50 μM) increased cAMP in the carotid body and these responses were absent in tyrosine hydroxylase-specific AC3 mutants. AC activators forskolin and 8-Bromo-cAMP enhanced ex vivo CB sensory response to hypoxia and H 2 S. The effects of 8-Bromo-cAMP were absent in Cnga2 mutants. Hypoxia and H 2 S stimulated ex vivo CB sensory activity and elevated intracellular calcium of glomus cells in wild type but not AC3 or Cnga2 mutants. Whole body plethysmography showed impaired ventilatory response to acute hypoxia (12%O 2 , 5 min) but not to hypercapnia in AC3 or Cnga2 mutants. The data suggest that AC3-cAMP-Cnga2 signaling contributes to H 2 S/Olfr78-dependent O 2 sensing by the CB to regulate breathing. Supported by NIH-HLBI P01-HL-44454 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.