The cAMP responsive element-binding protein (CREB) functions in a broad array of biological and pathophysiological processes. We found that saltinducible kinase 2 (SIK2) was abundantly expressed in neurons and suppressed CREB-mediated gene expression after oxygen-glucose deprivation (OGD). OGD induced the degradation of SIK2 protein concomitantly with the dephosphorylation of the CREB-specific coactivator transducer of regulated CREB activity 1 (TORC1), resulting in the activation of CREB and its downstream gene targets. Ca 2+ / calmodulin-dependent protein kinase I/IV are capable of phosphorylating SIK2 at Thr484, resulting in SIK2 degradation in cortical neurons. Neuronal survival after OGD was significantly increased in neurons isolated from sik2 À/À mice, and ischemic neuronal injury was significantly reduced in the brains of sik2 À/À mice subjected to transient focal ischemia. These findings suggest that SIK2 plays critical roles in neuronal survival, is modulated by CaMK I/IV, and regulates CREB via TORC1.
The (pro)renin receptor ((P)RR), which is a recently discovered molecule of the renin-angiotensin system, plays an important role in the development of cardiovascular diseases. However, the molecular properties and the subcellular distribution of (P)RR remain controversial. In this study, (P)RR-Venus in Chinese hamster ovary (CHO) cells ((P)RR-Venus-CHO) or endogenous (P)RR in human vascular smooth muscle cells (VSMC) were constitutively cleaved without any stimulation, and secretion of the aminoterminal fragment (NTF-(P)RR) into the media was determined using western blot analysis. Immunofluorescent analysis showed robust expression of (P)RR in the endoplasmic reticulum (ER) or the Golgi but not in the plasma membrane. Moreover, we identified ADAM19, which is expressed in the Golgi, as one of cleaving proteases of (P)RR. Transfected ADAM19 evoked the shedding of (P)RR, whereas transfected dominant negative ADAM19 suppressed it. Although (P)RR contains a furin cleavage site, neither the furin-deficient LoVo cells nor furin inhibitor-treated VSMC lost NTF-(P)RR in the media. The secreted NTF-(P)RR induced the renin activity of prorenin in the extracellular space. We describe that (P)RR is mainly localized in the subcellular organelles, such as the ER and Golgi, and (P)RR is cleaved by ADAM19 in the Golgi resulting in two fragments, NTF-(P)RR and CTF-(P)RR. These results may suggest that (P)RR is predominantly secreted into the extracellular space. Hypertension Research (2011) 34, 599-605; doi:10.1038/hr.2010.284; published online 27 January 2011Keywords: ADAM19; ectodomain shedding; (pro)renin receptor; renin-angiotensin system INTRODUCTION The (pro)renin receptor ((P)RR) is a recently discovered molecule of the renin-angiotensin system (RAS), which plays pivotal roles in the regulation of the cardiovascular system under normal and pathological conditions. (P)RR binds both renin and prorenin, which is the precursor form of renin. 1 Although the binding of renin to (P)RR may increase its catalytic activity, the binding affinity between (P)RR and renin is lower than that of (P)RR and prorenin. These results indicate that it may be necessary to focus on the interaction between (P)RR and prorenin. Prorenin does not display protease activity in the plasma because the enzymatic cleft is covered by the prosegment. 2 However, the binding of prorenin to (P)RR evokes the renin activity without removal of its prosegment. This nonproteolytic activation of prorenin contributes to the activation of the local RAS. In addition to the enzymatic activity, renin/prorenin has been shown to provide other (P)RR-mediated effects. 3 The binding of renin/prorenin to (P)RR induces the activation of intracellular signaling, including the p38 MAP kinase-HSP27 cascade, the PI3K pathway and the ERK 1/2 pathway; these effects occur independently of angiotensin II, which is a final product of RAS. 2,4,5 Although this evidence strongly supports (P)RR localization in the plasma membrane, the subcellular localization of (P)RR remains unknown. (P)R...
; A y ⁄ ⁄ a mice had brown hair, indicating that SIK2 represses eumelanogenesis in mice.
Background and Purpose-Arachidonic acid that is released following cerebral ischemia can be metabolized to . 20-HETE is a potent vasoconstrictor that may contribute to ischemic injury. This study examined the effects of blockading the synthesis of 20-HETE with TS-011 on infarct size after transient occlusion of the middle cerebral artery (MCAO) of rats and after thromboembolic stroke in monkeys. Methods-Rats were treated with TS-011 or vehicle at various times after MCAO. Infarct size was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining and plasma levels of 20-HETE were determined by liquid chromatography mass spectrometry (LC/MS). The effect of TS-011 on infarct size was also studied in monkeys after introduction of a clot into the internal carotid artery. Results-Plasma levels of 20-HETE increased after MCAO in rats. TS-011 (0.01 to 1.0 mg/kg per hour) reduced infarct volume by 40%. Chronic administration of TS-011 for 7 days reduced neurological deficits after MCAO in rats. TS-011 given in combination with tissue plasminogen activator also improved neurological outcome in the stroke model in monkeys. Conclusion-These results suggest that blockade of the formation of 20-HETE with TS-011 may be useful for the treatment of ischemic stroke.
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