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In mammals, the ventilatory response to decreased oxygen tension in the arterial blood is initiated by excitation of specialized O₂-sensitive chemoreceptor cells in the carotid body that release neurotransmitters to activate endings of the sinus nerve afferent fibers. We investigated the role of ATP acting via ionotropic P2X receptors in the carotid body function and ventilatory response to hypoxia in mice. Mice deficient in P2X₂ receptor subunit showed a markedly attenuated ventilatory response to hypoxia, whereas the response to hypoxia in P2X₃-deficient mice was comparable with that seen in wild-type controls. P2X₂ and P2X₃ receptor subunit deficiency did not affect the ventilatory responses to hypercapnia. P2X₂ subunit deficiency resulted in a dramatic reduction in the responses of the carotid sinus nerve to hypoxia in the in vitro carotid body-sinus nerve preparation. ATP and its stable analog α,β-methyleneATP …