title: PHYSIOLOGY. Regulation of breathing by CO₂ requires the proton-activated receptor GPR4 in retrotrapezoid nucleus neurons.
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.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Natasha N
authors.initials: NN
authors.lastname: Kumar
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, CH-8057, Switzerland.
authors.forename: Ana
authors.initials: A
authors.lastname: Velic
authors.affiliation: 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.
authors.forename: Jorge
authors.initials: J
authors.lastname: Soliz
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Yingtang
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Keyong
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA. Department of Physiology, Hebei Medical University, Shijiazhuang, Hebei, 050017, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Janelle L
authors.initials: JL
authors.lastname: Weaver
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Josh
authors.initials: J
authors.lastname: Sen
authors.affiliation: 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.
authors.forename: Stephen B G
authors.initials: SB
authors.lastname: Abbott
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Roman M
authors.initials: RM
authors.lastname: Lazarenko
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, CH-4002, Switzerland.
authors.forename: Marie-Gabrielle
authors.initials: MG
authors.lastname: Ludwig
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Perez-Reyes
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, CH-8057, Switzerland.
authors.forename: Nilufar
authors.initials: N
authors.lastname: Mohebbi
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, CH-8057, Switzerland.
authors.forename: Carla
authors.initials: C
authors.lastname: Bettoni
authors.affiliation: Institute of Veterinary Physiology, University of Zurich, Zurich, CH-8057, Switzerland.
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, CH-4002, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Suply
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, CH-4002, Switzerland.
authors.forename: Klaus
authors.initials: K
authors.lastname: Seuwen
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Patrice G
authors.initials: PG
authors.lastname: Guyenet
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, CH-8057, Switzerland. Wagnerca@access.uzh.ch bayliss@virginia.edu.
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA. Wagnerca@access.uzh.ch bayliss@virginia.edu.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bayliss
mesh_terms: D000142:Acidosis, Respiratory / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D002245:Carbon Dioxide / Q000502:physiology*; D005260:Female; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D012119:Respiration; D065833:Trapezoid Body / Q000166:cytology / Q000378:metabolism / Q000502:physiology*
chemical_list: C517811:GPR4 protein, mouse; C498739:Kcnk5 protein, mouse; D024683:Potassium Channels, Tandem Pore Domain; D043562:Receptors, G-Protein-Coupled; D002245:Carbon Dioxide