title: Expression of the CHOP-inducible carbonic anhydrase CAVI-b is required for BDNF-mediated protection from hypoxia.
abstract: Carbonic anhydrases (CAs) comprise a family of zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide. CAs contribute to a myriad of physiological processes, including pH regulation, anion transport and water balance. To date, 16 known members of the mammalian alpha-CA family have been identified. Given that the catalytic family members share identical reaction chemistry, their physiologic roles are influenced greatly by their tissue and sub-cellular locations. CAVI is the lone secreted CA and exists in both saliva and the gastrointestinal mucosa. An alternative, stress-inducible isoform of CAVI (CAVI-b) has been shown to be expressed from a cryptic promoter that is activated by the CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP). The CAVI-b isoform is not secreted and is currently of unknown physiological function. Here we use neuronal models, including a model derived using Car6 and CHOP gene ablations, to delineate a role for CAVI-b in ischemic protection. Our results demonstrate that CAVI-b expression, which is increased through CHOP-signaling in response to unfolded protein stress, is also increased by oxygen-glucose deprivation (OGD). While enforced expression of CAVI-b is not sufficient to protect against ischemia, CHOP regulation of CAVI-b is necessary for adaptive changes mediated by BDNF that reduce subsequent ischemic damage. These results suggest that CAVI-b comprises a necessary component of a larger adaptive signaling pathway downstream of CHOP.
authors.affiliation: Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Tori A
authors.initials: TA
authors.lastname: Matthews
authors.affiliation: Undergraduate Program in Neuroscience, University of Rochester, Rochester, NY, USA.
authors.forename: Allyssa
authors.initials: A
authors.lastname: Abel
authors.affiliation: Undergraduate Program in Cell and Developmental Biology, University of Rochester, Rochester, NY, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Demme
authors.affiliation: Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Sherman
authors.affiliation: Institute of Biomedical Technology and School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: Pei-wen
authors.initials: PW
authors.lastname: Pan
authors.affiliation: Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Marc W
authors.initials: MW
authors.lastname: Halterman
authors.affiliation: Institute of Biomedical Technology and School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Parkkila
authors.affiliation: Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA; Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA. Electronic address: keith_nehrke@urmc.rochester.edu.
authors.forename: Keith
authors.initials: K
authors.lastname: Nehrke
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000172:deficiency / Q000378:metabolism*; D002454:Cell Differentiation; D015687:Cell Hypoxia / Q000187:drug effects*; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D005947:Glucose / Q000172:deficiency; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C497250:Ddit3 protein, mouse; D020033:Protein Isoforms; D051742:Transcription Factor CHOP; D007770:L-Lactate Dehydrogenase; D002256:Carbonic Anhydrases; C477051:carbonic anhydrase VI; D005947:Glucose
keywords: Brain-derived neurotrophic factor (BDNF); Carbonic anhydrase; Ischemia; Neurosphere; Oxygen glucose deprivation (OGD); Unfolded protein response (UPR)