The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Melatonin modulates nitric oxide-regulated WNK-SPAK/OSR-1-NKCC1 signaling in dorsal raphe nucleus of rats

  • Yang, Hye Jin (Department of Biomedical Science, Graduate School, Kyung Hee University) ;
  • Kim, Mi Jung (Department of Physiology, College of Medicine, Kyung Hee University) ;
  • Kim, Sung Soo (Biomedical Science Institute and Medical Research Center for Reactive Oxygen Species, College of Medicine, Kyung Hee University) ;
  • Cho, Young-Wuk (Department of Biomedical Science, Graduate School, Kyung Hee University)
  • Received : 2021.03.11
  • Accepted : 2021.07.20
  • Published : 2021.09.01
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Abstract

The sleep-wake cycle is regulated by the alternating activity of sleep- and wake-promoting neurons. The dorsal raphe nucleus (DRN) secretes 5-hydroxytryptamine (5-HT, serotonin), promoting wakefulness. Melatonin secreted from the pineal gland also promotes wakefulness in rats. Our laboratory recently demonstrated that daily changes in nitric oxide (NO) production regulates a signaling pathway involving with-no-lysine kinase (WNK), Ste20-related proline alanine rich kinase (SPAK)/oxidative stress response kinase 1 (OSR1), and cation-chloride co-transporters (CCC) in rat DRN serotonergic neurons. This study was designed to investigate the effect of melatonin on NO-regulated WNK-SPAK/OSR1-CCC signaling in wake-inducing DRN neurons to elucidate the mechanism underlying melatonin's wake-promoting actions in rats. Ex vivo treatment of DRN slices with melatonin suppressed neuronal nitric oxide synthase (nNOS) expression and increased WNK4 expression without altering WNK1, 2, or 3. Melatonin increased phosphorylation of OSR1 and the expression of sodium-potassium-chloride co-transporter 1 (NKCC1), while potassium-chloride co-transporter 2 (KCC2) remained unchanged. Melatonin increased the expression of tryptophan hydroxylase 2 (TPH2, serotonin-synthesizing enzyme). The present study suggests that melatonin may promote its wakefulness by modulating NO-regulated WNK-SPAK/OSR1-KNCC1 signaling in rat DRN serotonergic neurons.

Keywords

Acknowledgement

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (nos. 2011-0030072 and 2011-0011939).

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