Activation of Orexin System Stimulates CaMKII Expression

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.

Hypocretin/orexin influences chronic sleep disruption injury in the hippocampus

“…Additionally, HCRT exogenously applied to a neural cell line (SH-SH5Y cells) in culture can impart mitochondrial dysfunction and injury and increases oxidative stress ( Li et al, 2020 ; Zhu et al, 2021 ), which may then promote Aβ production ( Plascencia-Villa and Perry, 2021 ). HCRT-1 (orexin-A) peptide upregulates calcium/calmodulin-dependent kinase II (CaMKII), which can then phosphorylate tau and modulate Aβ synaptotoxicity ( Oka et al, 2017 ; Opazo et al, 2018 ; Fan et al, 2021 ). Whether HCRT impairs CFS microglial function and whether CFS increases HCRT to levels required to induce mitochondrial injury and/or CAMKII activation should now be examined.…”

Orexin, Sleep, Sympathetic Neural Activity, and Cardiovascular Function

“…32 Previous studies report that orexin-mediated CaMKII activation within the rat PVN can result in elevations of sympathetic nerve activity and blood pressure. 32,52 Orexins may also act through activation of the sodium-calcium exchanger 53 or suppression of potassium efflux 54 to further postsynaptically modify neuronal excitability. Many orexin neurons are glutamatergic and can also release glutamate to facilitate neuronal excitation.…”

“…49,50 Ca 2+ is an important secondary messenger, which can in turn activate many Ca 2+ -sensitive enzymes including calcium/CaMKII (calmodulin-dependent protein kinase II). 32 Previous studies report that orexin-mediated CaMKII activation within the rat PVN can result in elevations of sympathetic nerve activity and blood pressure. 32,52 Orexins may also act through activation of the sodium-calcium exchanger 53 or suppression of potassium efflux 54 to further postsynaptically modify neuronal excitability.…”

“…28 Conversely, other regions of the brain, including the serotonergic dorsal raphe, the PVN, and the rostral ventrolateral medulla, express both OX1R and OX2R. [28][29][30][31][32][33] In the brain, orexin receptors are primary distributed in neurons. 32 One recent study reported that PVN OX1Rs are also co-localized with astrocytes.…”

the inhibitory effect of Orexin system on different diseases through mTOR signaling pathway

“…OX1R is preferentially expressed in the locus coeruleus (LC), while OX2R is mainly distributed in the nodular papillary nucleus (TMN). The selectivity of Orexin for oxygen free radicals and the different distribution of receptors may be the reasons for the different physiological effects of the Orexin/receptor pathway [15]. There are two receptors for orexin factor, OX1R and OX2R, respectively.…”