期刊
SCIENCE
卷 348, 期 6240, 页码 1255-1260出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaa0922
关键词
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资金
- National Health and Medical Research Council of Australia Early Career Fellowship [GNT1052674]
- Swiss National Science Foundation [31003A_155959/1]
- National Institutes of Health [HL074011, HL108609]
- Novartis [GPR65, GPR4 KO]
Blood gas and tissue pH regulation depend on the ability of the brain to sense CO2 and/or H+ and alter breathing appropriately, a homeostatic process called central respiratory chemosensitivity. We show that selective expression of the proton-activated receptor GPR4 in chemosensory neurons of the mouse retrotrapezoid nucleus (wRTN) is required for CO2-stimulated breathing. Genetic deletion of GPR4 disrupted acidosis-dependent activation of RTN neurons, increased apnea frequency, and blunted ventilatory responses to CO2. Reintroduction of GPR4 into RTN neurons restored CO2-dependent RTN neuronal activation and rescued the ventilatory phenotype. Additional elimination of TASK-2 (K(2P)5), a pH-sensitive K+ channel expressed in RTN neurons, essentially abolished the ventilatory response to CO2. The data identify GPR4 and TASK-2 as distinct, parallel, and essential central mediators of respiratory chemosensitivity.
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