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      PHYSIOLOGY. Regulation of breathing by CO₂ requires the proton-activated receptor GPR4 in retrotrapezoid nucleus neurons.

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          Abstract

          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 (RTN) 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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          Author and article information

          Journal
          Science
          Science (New York, N.Y.)
          1095-9203
          0036-8075
          Jun 12 2015
          : 348
          : 6240
          Affiliations
          [1 ] Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
          [2 ] Institute of Physiology, University of Zurich, Zurich, CH-8057, Switzerland.
          [3 ] Institute of Veterinary Physiology, University of Zurich, Zurich, CH-8057, Switzerland. Centre de Recherche du CHU de Québec, Département de Pédiatrie, Faculté de Médecine, Université Laval, Québec, QC, Canada.
          [4 ] Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA. Department of Physiology, Hebei Medical University, Shijiazhuang, Hebei, 050017, China.
          [5 ] Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA. School of Medical Sciences, University of New South Wales, New South Wales 2052, Australia. Department of Neurology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
          [6 ] Novartis Institutes for Biomedical Research, Basel, CH-4002, Switzerland.
          [7 ] Institute of Veterinary Physiology, University of Zurich, Zurich, CH-8057, Switzerland.
          [8 ] Institute of Physiology, University of Zurich, Zurich, CH-8057, Switzerland. Wagnerca@access.uzh.ch bayliss@virginia.edu.
          [9 ] Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA. Wagnerca@access.uzh.ch bayliss@virginia.edu.
          Article
          348/6240/1255
          10.1126/science.aaa0922
          26068853
          Copyright © 2015, American Association for the Advancement of Science.

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