title: Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and β-Arrestin-1-Regulated Lactate Metabolism.
abstract: Stress is a conserved physiological response in mammals. Whereas moderate stress strengthens memory to improve reactions to previously experienced difficult situations, too much stress is harmful.
  
  
  
  We used specific β-adrenergic agonists, as well as β2-adrenergic receptor (β2AR) and arrestin knockout models, to study the effects of adaptive β2AR activation on cognitive function using Morris water maze and object recognition experiments. We used molecular and cell biological approaches to elucidate the signaling subnetworks.
  
  
  
  We observed that the duration of the adaptive β2AR activation determines its consequences on learning and memory. Short-term formoterol treatment, for 3 to 5 days, improved cognitive function; however, prolonged β2AR activation, for more than 6 days, produced harmful effects. We identified the activation of several signaling networks downstream of β2AR, as well as an essential role for arrestin and lactate metabolism in promoting cognitive ability. Whereas Gs-protein kinase A-cyclic adenosine monophosphate response element binding protein signaling modulated monocarboxylate transporter 1 expression, β-arrestin-1 controlled expression levels of monocarboxylate transporter 4 and lactate dehydrogenase A through the formation of a β-arrestin-1/phospho-mitogen-activated protein kinase/hypoxia-inducible factor-1α ternary complex to upregulate lactate metabolism in astrocyte-derived U251 cells. Conversely, long-term treatment with formoterol led to the desensitization of β2ARs, which was responsible for its decreased beneficial effects.
  
  
  
  Our results not only revealed that β-arrestin-1 regulated lactate metabolism to contribute to β2AR functions in improved memory formation, but also indicated that the appropriate management of one specific stress pathway, such as through the clinical drug formoterol, may exert beneficial effects on cognitive abilities.
authors.affiliation: Key Laboratory Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, China; Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, China.
authors.forename: Jun-Hong
authors.initials: JH
authors.lastname: Dong
authors.affiliation: Key Laboratory Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, China; Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, China.
authors.forename: Yi-Jing
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Physiology, Shandong University School of Medicine, China.
authors.forename: Min
authors.initials: M
authors.lastname: Cui
authors.affiliation: Cell Biology, Shandong University School of Medicine, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Physiology, Shandong University School of Medicine, China.
authors.forename: Wen-Shuai
authors.initials: WS
authors.lastname: Zheng
authors.affiliation: Key Laboratory Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, China; Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, China.
authors.forename: Ming-Liang
authors.initials: ML
authors.lastname: Ma
authors.affiliation: Key Laboratory Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Key Laboratory Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, China; Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, China; Physiology, Shandong University School of Medicine, China.
authors.forename: Dong-Fang
authors.initials: DF
authors.lastname: He
authors.affiliation: Key Laboratory Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, China; Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, China.
authors.forename: Qiao-Xia
authors.initials: QX
authors.lastname: Hu
authors.affiliation: Key Laboratory Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, China; Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, China; Physiology, Shandong University School of Medicine, China.
authors.forename: Dao-Lai
authors.initials: DL
authors.lastname: Zhang
authors.affiliation: Key Laboratory Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, China; Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, China; Qilu Hospital, Shandong University, Jinan, Shandong, China.
authors.forename: Shang-Lei
authors.initials: SL
authors.lastname: Ning
authors.affiliation: Physiology, Shandong University School of Medicine, China.
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Neurobiology, Shandong University School of Medicine, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Zhejiang University, Institute of Neuroscience, China.
authors.forename: Xiang-Yao
authors.initials: XY
authors.lastname: Li
authors.affiliation: Key Laboratory Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yi
authors.affiliation: Duke University, School of Medicine, Durham, North Carolina.
authors.forename: Amy
authors.initials: A
authors.lastname: Lin
authors.affiliation: Duke University, School of Medicine, Durham, North Carolina.
authors.forename: Alem W
authors.initials: AW
authors.lastname: Kahsai
authors.affiliation: Duke University, School of Medicine, Durham, North Carolina.
authors.forename: Thomas Joseph
authors.initials: TJ
authors.lastname: Cahill
authors.affiliation: Neurobiology, Shandong University School of Medicine, China.
authors.forename: Zhe-Yu
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: Key Laboratory Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, China; Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.affiliation: Key Laboratory Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, China; Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, China; Duke University, School of Medicine, Durham, North Carolina. Electronic address: sunjinpeng@sdu.edu.cn.
authors.forename: Jin-Peng
authors.initials: JP
authors.lastname: Sun
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002460:Cell Line; D000068759:Formoterol Fumarate / Q000008:administration & dosage; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid / Q000378:metabolism*; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction; D013315:Stress, Psychological / Q000378:metabolism*; D059467:Transcriptome; D000071559:beta-Arrestin 1 / Q000378:metabolism*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D018343:Receptors, Adrenergic, beta-2; C498648:Slc16a4 protein, mouse; D000071559:beta-Arrestin 1; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D019205:GTP-Binding Protein alpha Subunits, Gs; D000068759:Formoterol Fumarate
keywords: Adrenergic receptor; Arrestin; G protein; HIF-1α; Memory; Stress