期刊
ASN NEURO
卷 13, 期 -, 页码 -出版社
SAGE PUBLICATIONS LTD
DOI: 10.1177/1759091420984920
关键词
G-substrate; phase advance; protein phosphatase 2A; suprachiasmatic nuclei
资金
- Ministerio de Ciencia, Tecnologia e Innovacion, Agencia Nacional de Promocion de la Investigacion, el Desarrollo Tecnologico y la Innovacion, Argentina [PICT 2099-2014]
- Universidad Nacional de Quilmes, Argentina [PUNQ 1310/19]
- JSPS, Japan [19K22834, 19H04044]
- Grants-in-Aid for Scientific Research [19H04044, 19K22834] Funding Source: KAKEN
In this study, the researchers investigated the role of G-substrate as a downstream effector in the NO/cGMP/PKG photic pathway in the hamster SCN. They found that phosphorylated G-substrate (p-GS) could act as a protein phosphatase 2 A (PP2A) inhibitor, and demonstrated a physical interaction between p-GS and PP2A in SCN homogenates. Moreover, they showed that GS phosphorylation increased after light pulses and intraperitoneal treatment with an inhibitor of phosphodiesterase 5, while treatment with a PKG inhibitor reduced photic phosphorylation of GS.
The mammalian circadian clock at the hypothalamic suprachiasmatic nuclei (SCN) entrains biological rhythms to the 24-h cyclic environment, by encoding light-dark transitions in SCN neurons. Light pulses induce phase shifts in the clock and in circadian rhythms; photic signaling for circadian phase advances involves a nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (PKG) pathway, increasing the expression of Period (Per) genes. Effectors downstream of PKG remain unknown. Here we investigate the role of G-substrate (GS), a PKG substrate, in the hamster SCN. GS and phosphorylated G-substrate (p-GS) were present in a subset of SCN cells. Moreover, GS phosphorylation (p-GS/GS ratio) increased in SCN homogenates after light pulses delivered at circadian time (CT) 18 and intraperitoneal treatment with sildenafil, an inhibitor of phosphodiesterase 5 (a cGMP-specific phosphodiesterase). On the other hand, intracerebroventricular treatment with the PKG inhibitor KT5823, reduced photic phosphorylation of GS to basal levels. Since p-GS could act as a protein phosphatase 2 A (PP2A) inhibitor, we demonstrated physical interaction between p-GS and PP2A in SCN homogenates, and also a light-pulse dependent decrease of PP2A activity. Intracerebroventricular treatment with okadaic acid, a PP2A inhibitor, increased the magnitude of light-induced phase advances of locomotor rhythms. We provide evidence on the physiological phosphorylation of GS as a new downstream effector in the NO/cGMP/PKG photic pathway in the hamster SCN, including its role as a PP2A inhibitor.
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