Activation of Orexin System Stimulates CaMKII Expression

Yuanyuan Fan; Enshe Jiang; Huanjia Gao; Jeremy Bigalke; Bojun Chen; Chunxiu Yu; Qinghui Chen; Zhiying Shan

doi:10.3389/fphys.2021.698185

Activation of Orexin System Stimulates CaMKII Expression

Front Physiol. 2021 Jul 1:12:698185. doi: 10.3389/fphys.2021.698185. eCollection 2021.

Authors

Yuanyuan Fan^{1

2}, Enshe Jiang^{1

3}, Huanjia Gao^{1

4}, Jeremy Bigalke¹, Bojun Chen⁵, Chunxiu Yu^{6

7}, Qinghui Chen^{1

6}, Zhiying Shan^{1

6}

Affiliations

¹ Department of Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, MI, United States.
² School of Life Sciences, Henan University, Kaifeng, China.
³ Institute of Nursing and Health, Henan University, Kaifeng, China.
⁴ The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China.
⁵ Department of Emergency, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.
⁶ Health Research Institute, Michigan Technological University, Houghton, MI, United States.
⁷ Department of Biological Sciences, Michigan Technological University, Houghton, MI, United States.

Abstract

Hyperactivity of the orexin system within the paraventricular nucleus (PVN) has been shown to contribute to increased sympathetic nerve activity (SNA) and blood pressure (BP) in rodent animals. However, the underlying molecular mechanisms remain unclear. Here, we test the hypothesis that orexin system activation stimulates calcium/calmodulin-dependent kinase II (CaMKII) expression and activation, and stimulation of CaMKII expressing PVN neurons increases SNA and BP. Real-time PCR and/or western blot were carried out to test the effect of orexin-A administration on CaMKII expression in the PVN of normal Sprague Dawley (SD) rats and orexin receptor 1 (OX1R) expressing PC12 cells. Immunostaining was performed to assess OX1R cellular localization in the PVN of SD rats as well as orexin-A treatment on CaMKII activation in cultured hypothalamic neurons. In vivo sympathetic nerve recordings were employed to test the impact of optogenetic stimulation of CaMKII-expressing PVN neurons on the renal SNA (RSNA) and BP. The results showed that intracerebroventricular injection of orexin-A into the SD rat increases mRNA expression of CaMKII subunits in the PVN. In addition, Orexin-A treatment increases CaMKII expression and its phosphorylation in OX1R-expressing PC12 cells. Furthermore, Orexin-A treatment increases CaMKII activation in cultured hypothalamic neurons from neonatal SD rats. Finally, optogenetic excitation of PVN CaMKII-expressing neurons results in robust increases in RSNA and BP in SD rats. Our results suggest that increased orexin system activity activates CaMKII expression in cardiovascular relevant regions, and this may be relevant to the downstream cardiovascular effects of CaMKII.

Keywords: CaMKII; blood pressure; orexin-A; paraventricular nucleus; sympathetic nerve activity.

Abstract

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