title: Essential role of hemoglobin beta-93-cysteine in posthypoxia facilitation of breathing in conscious mice.
abstract: When erythrocyte hemoglobin (Hb) is fully saturated with O2, nitric oxide (NO) covalently binds to the cysteine 93 residue of the Hb β-chain (B93-CYS), forming S-nitrosohemoglobin. Binding of NO is allosterically coupled to the O2 saturation of Hb. As saturation falls, the NO group on B93-CYS is transferred to thiols in the erythrocyte, and in the plasma, forming circulating S-nitrosothiols. Here, we studied whether the changes in ventilation during and following exposure to a hypoxic challenge were dependent on erythrocytic B93-CYS. Studies were performed in conscious mice in which native murine Hb was replaced with human Hb (hB93-CYS mice) and in mice in which murine Hb was replaced with human Hb containing an alanine rather than cysteine at position 93 on the Bchain (hB93-ALA). Both strains expressed human γ-chain Hb, likely allowing a residual element of S-nitrosothiol-dependent signaling. While resting parameters and initial hypoxic (10% O2, 90% N2) ventilatory responses were similar in hB93-CYS mice and hB93-ALA mice, the excitatory ventilatory responses (short-term potentiation) that occurred once the mice were returned to room air were markedly diminished in hB93-ALA mice. Further, short-term potentiation responses were virtually absent in mice with bilateral transection of the carotid sinus nerves. These data demonstrate that hB93-CYS plays an essential role in mediating carotid sinus nerve-dependent short-term potentiation, an important mechanism for recovery from acute hypoxia.
authors.affiliation: Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, Virginia; bmg46@case.edu.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gaston
authors.affiliation: Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Walter J
authors.initials: WJ
authors.lastname: May
authors.affiliation: Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Spencer
authors.initials: S
authors.lastname: Sullivan
authors.affiliation: Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Sean
authors.initials: S
authors.lastname: Yemen
authors.affiliation: Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Nadzeya V
authors.initials: NV
authors.lastname: Marozkina
authors.affiliation: Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Palmer
authors.affiliation: Department of Anesthesia, University of Iowa Hospitals and Clinics, Iowa City, Iowa; and.
authors.forename: James N
authors.initials: JN
authors.lastname: Bates
authors.affiliation: Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, Ohio.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lewis
mesh_terms: D000818:Animals; D002346:Carotid Sinus / Q000503:physiopathology*; D003243:Consciousness; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism*; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism*; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012123:Pulmonary Ventilation; D015656:Respiratory Mechanics; D013329:Structure-Activity Relationship
chemical_list: D006454:Hemoglobins; D003545:Cysteine
keywords: S-nitrosothiol; S-nitrosylation; hemoglobin; hypoxia; posthypoxia; ventilation