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Role of G-Substrate in the NO/cGMP/PKG Signal Transduction Pathway for Photic Entrainment of the Hamster Circadian Clock
ASN Neuro ( IF 4.7 ) Pub Date : 2021-01-11 , DOI: 10.1177/1759091420984920
Santiago Andrés Plano 1, 2 , María Soledad Alessandro 2 , Laura Lucía Trebucq 2 , Shogo Endo 3 , Diego Andrés Golombek 2 , Juan José Chiesa 2
Affiliation  

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.



中文翻译:

G-底物在 NO/cGMP/PKG 信号转导通路中对仓鼠昼夜节律钟光牵引的作用

下丘脑视交叉上核 (SCN) 的哺乳动物生物钟通过编码 SCN 神经元中的明暗转换,将生物节律带入 24 小时循环环境。光脉冲引起时钟和昼夜节律的相移;昼夜节律阶段进展的光信号涉及一氧化氮 (NO)/环磷酸鸟苷 (cGMP)/cGMP 依赖性蛋白激酶 (PKG) 途径,增加周期的表达 ( Per) 基因。PKG 下游的效应器仍然未知。在这里,我们研究了 G 底物 (GS),一种 PKG 底物,在仓鼠 SCN 中的作用。GS 和磷酸化 G 底物 (p-GS) 存在于 SCN 细胞的一个子集中。此外,在昼夜节律时间 (CT) 18 递送光脉冲和用磷酸二酯酶 5(一种 cGMP 特异性磷酸二酯酶)抑制剂西地那非腹膜内治疗后,SCN 匀浆中的 GS 磷酸化(p-GS/GS 比率)增加。另一方面,用 PKG 抑制剂 KT5823 进行脑室内治疗,可将 GS 的光磷酸化降低至基础水平。由于 p-GS 可以作为蛋白磷酸酶 2 A (PP2A) 抑制剂,我们证明了 SCN 匀浆中 p-GS 和 PP2A 之间的物理相互作用,以及 PP2A 活性的光脉冲依赖性降低。用 PP2A 抑制剂冈田酸进行脑室内治疗,增加了光诱导运动节律的相位进展幅度。我们提供了 GS 的生理磷酸化作为仓鼠 SCN 中 NO/cGMP/PKG 光通路中新的下游效应子的证据,包括其作为 PP2A 抑制剂的作用。

更新日期:2021-01-12
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