Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and ß-Arrestin-1-Regulated Lactate Metabolism.
Biol Psychiatry
; 81(8): 654-670, 2017 04 15.
Article
em En
| MEDLINE
| ID: mdl-27916196
ABSTRACT
BACKGROUND:
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.METHODS:
We used specific ß-adrenergic agonists, as well as ß2-adrenergic receptor (ß2AR) and arrestin knockout models, to study the effects of adaptive ß2AR activation on cognitive function using Morris water maze and object recognition experiments. We used molecular and cell biological approaches to elucidate the signaling subnetworks.RESULTS:
We observed that the duration of the adaptive ß2AR activation determines its consequences on learning and memory. Short-term formoterol treatment, for 3 to 5 days, improved cognitive function; however, prolonged ß2AR activation, for more than 6 days, produced harmful effects. We identified the activation of several signaling networks downstream of ß2AR, 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, ß-arrestin-1 controlled expression levels of monocarboxylate transporter 4 and lactate dehydrogenase A through the formation of a ß-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 ß2ARs, which was responsible for its decreased beneficial effects.CONCLUSIONS:
Our results not only revealed that ß-arrestin-1 regulated lactate metabolism to contribute to ß2AR 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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Estresse Psicológico
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Transdução de Sinais
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Receptores Adrenérgicos beta 2
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Ácido Láctico
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Subunidades alfa Gs de Proteínas de Ligação ao GTP
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Beta-Arrestina 1
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Aprendizagem
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Memória
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Biol Psychiatry
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
China
País de publicação:
EEUU
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ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA