Effects of cyclosporin A, FK506 and rapamycin on calcineurin phosphatase activity in mouse brain

Yu, Dayu; Luo, Jing; Bu, Fan; Zhang, Wen; Wang, Qun

doi:10.1080/15216540600791555

Cited by 21 publications

(17 citation statements)

References 13 publications

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“…To test the involvement of calcineurin in sFlt-1 production, pregnant mice were infused with Ang II with or without daily subcutaneous injection of FK506, a well-known selective calcineurin inhibitor. 29,30 As shown in Figure 4A, the increased sFlt-1 secretion induced by Ang II at gestation days 15 and 17 was completely inhibited by FK506, indicating that the induction of sFlt-1 by Ang II is mediated through calcineurin signaling in vivo. We also found that FK506 is able to attenuate the elevated systolic blood pressure and reduced fetal growth resulting from Ang II infusion (Table).…”

Section: At 1 Receptor Activation Induces Sflt-1 Release Via the Calcmentioning

confidence: 95%

Angiotensin II Induces Soluble fms-Like Tyrosine Kinase-1 Release via Calcineurin Signaling Pathway in Pregnancy

Zhou

Ahmad

et al. 2007

Circulation Research

148

114

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Abstract-Maternal endothelial dysfunction in preeclampsia is associated with increased soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor and placental growth factor. Angiotensin II (Ang II) is a potent vasoconstrictor that increases concomitant with sFlt-1 during pregnancy. Therefore, we speculated that Ang II may promote the expression of sFlt-1 in pregnancy. Here we report that infusion of Ang II significantly increases circulating levels of sFlt-1 in pregnant mice, thereby demonstrating that Ang II is a regulator of sFlt-1 secretion in vivo. Furthermore, Ang II stimulated sFlt-1 production in a dose-and time-dependent manner from human villous explants and cultured trophoblasts but not from endothelial cells, suggesting that trophoblasts are the primary source of sFlt-1 during pregnancy. As expected, Ang II-induced sFlt-1 secretion resulted in the inhibition of endothelial cell migration and in vitro tube formation. In vitro and in vivo studies with losartan, small interfering RNA specific for calcineurin and FK506 demonstrated that Ang II-mediated sFlt-1 release was via Ang II type 1 receptor activation and calcineurin signaling, respectively. These findings reveal a previously unrecognized regulatory role for Ang II on sFlt-1 expression in murine and human pregnancy and suggest that elevated sFlt-1 levels in preeclampsia may be caused by a dysregulation of the local renin/angiotensin system. (Circ Res. 2007;100:88-95.)

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Section: At 1 Receptor Activation Induces Sflt-1 Release Via the Calcmentioning

confidence: 95%

Angiotensin II Induces Soluble fms-Like Tyrosine Kinase-1 Release via Calcineurin Signaling Pathway in Pregnancy

Zhou

Ahmad

et al. 2007

Circulation Research

148

114

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“…To further confirm that these behavioral effects were specific to calcineurin inhibition, we performed a negative control experiment with rapamycin, which binds to FKBP but does not inhibit calcineurin activity (Liu et al, 1991;Yu et al, 2006). Once again, nicotine administration led to locomotor sensitization across testing days (F (3,27) ϭ 2.944; p ϭ 0.05) (Fig.…”

Section: Calcineurin Inhibition In the Vta Attenuates Nicotine-mediatmentioning

confidence: 99%

Role of Calcineurin in Nicotine-Mediated Locomotor Sensitization

Addy¹,

Fornasiero²,

Stevens³

et al. 2007

J. Neurosci.

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Calcineurin is a serine/threonine phosphatase that contributes to the effects of nicotine on calcium signaling in cultured cortical neurons; however, the role of calcineurin in behavioral responses to nicotine in vivo has not been examined. We therefore determined whether calcineurin blockade could alter nicotine-mediated locomotor sensitization in Sprague Dawley rats using systemic or brain regionspecific administration of the calcineurin inhibitors cyclosporine or FK506. Systemic cyclosporine administration decreased calcineurin activity in the brain, attenuated nicotine-mediated locomotor sensitization, and blocked the effects of nicotine on DARPP32 (dopamineand cAMP-regulated phosphoprotein-32) activation in the striatum. Direct infusion of calcineurin inhibitors cyclosporine or FK506 into the ventral tegmental area (VTA) also attenuated nicotine-mediated locomotor sensitization, whereas infusion of rapamycin, which binds to FK-binding protein but does not inhibit calcineurin, did not affect sensitization. Together, the data suggest that activation of calcineurin, particularly in the VTA, is a novel signaling event important for nicotine-mediated behavior and intracellular signaling.

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“…In addition, since cyclosporine is an immunophilin which must bind to cyclophilin in order to inhibit calcineurin (Liu et al 1991), it is possible our results could be due to the immunophilin effects of cyclosporine that are independent of calcineurin inhibition. To address this possibility, we performed an additional experiment with rapamycin, an immunophilin that does not inhibit calcineurin (Liu et al 1991;Yu et al 2006). While control animals showed enhanced locomotor activity upon acute cocaine injection (Rap 0 mg, p < 0.05, independent samples ttest, Fig 2D), pretreatment with rapamycin (15 mg/kg) did not affect cocaine-induced locomotor activity (p > 0.05, independent samples t-test, Fig 2D).…”

Section: Systemic Cyclosporine Pretreatment Leads To a Sensitized Locmentioning

confidence: 99%

Administration of the calcineurin inhibitor cyclosporine modulates cocaine-induced locomotor activity in rats

et al. 2008

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Rationale-Cocaine administration in rats increases locomotor activity as a result of underlying changes in neurotransmitter dynamics and intracellular signaling. The serine/ threonine phosphatase, calcineurin, is known to modulate several signaling proteins that can influence behavioral responses to cocaine.Objective-This study aimed to determine whether calcineurin plays a role in locomotor responses associated with acute and repeated cocaine exposure. Second, we examined cocaine-mediated changes in intracellular signaling in order to identify potential mechanism underlying the ability of calcineurin to influence cocaine-mediated behavior.Methods-Locomotor activity was assessed over 17 days in male Sprague-Dawley rats (n=48) that received daily administration of cocaine (15 mg/kg, s.c.) or saline in the presence or absence of the calcineurin inhibitor, cyclosporine (15 mg/kg, i.p.). Non-cocaine treated animals from this initial experiment (n=24) also received an acute cocaine challenge on day 18 of testing.Results-Daily cyclosporine administration potentiated the locomotor response to repeated cocaine 5 mins after cocaine injection and attenuated the sustained locomotor response 15 to 40 mins after cocaine. Further, cyclosporine pretreatment for 17 days augmented the acute locomotor response to acute cocaine 5 to 30 mins after cocaine injection. Finally, repeated exposure to either cocaine or cyclosporine for 22 days increased synapsin I phosphorylation at the calcineurin sensitive Ser 62/67 site, demonstrating a common downstream target for both calcineurin and cocaine.Conclusion-Our results suggest that calcineurin inhibition augments locomotor responses to cocaine and mimics cocaine-mediated phosphorylation of synapsin I.

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Effects of cyclosporin A, FK506 and rapamycin on calcineurin phosphatase activity in mouse brain

Cited by 21 publications

References 13 publications

Angiotensin II Induces Soluble fms-Like Tyrosine Kinase-1 Release via Calcineurin Signaling Pathway in Pregnancy

Angiotensin II Induces Soluble fms-Like Tyrosine Kinase-1 Release via Calcineurin Signaling Pathway in Pregnancy

Role of Calcineurin in Nicotine-Mediated Locomotor Sensitization

Administration of the calcineurin inhibitor cyclosporine modulates cocaine-induced locomotor activity in rats

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