Inhibition of excitatory neuronal cell death by cell‐permeable calcineurin autoinhibitory peptide

Terada, Hiroaki; Matsushita, Masayuki; Lu, Yun; Shirai, Takeshi; Li, Shengtian; Tomizawa, Kazuhito; Moriwaki, Akiyoshi; Nishio, Shinsaku; Date, Isao; Ohmoto, Takashi; Matsui, Hideki

doi:10.1046/j.1471-4159.2003.02098.x

Cited by 34 publications

(29 citation statements)

References 37 publications

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“…4, A and B). Notably, 50% inhibition of chymotrypsin was noted using 10 M CiP, which approximates its IC 50 (8 M) in neuronal cells (40). Together, the results using inhibitors FK506 and CiP indicate a role for calcineurin in intra-acinar zymogen activation.…”

Section: Chymotrypsin Activation Is Dependent On a Rise In Ca Imentioning

confidence: 60%

“…To confirm the specificity of FK506, cell-permeable CiP was used. It was made cell permeable by covalently attaching a poly-arginine-based protein transduction domain (11R) (40). Once inside the cell, CiP inhibits calcineurin by a different mechanism than FK506; it mimics the endogenous autoinhibitory domain of the calcineurin A subunit and blocks its catalytic activity (28).…”

Section: Chymotrypsin Activation Is Dependent On a Rise In Ca Imentioning

confidence: 99%

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Caerulein-induced intracellular pancreatic zymogen activation is dependent on calcineurin

Husain¹,

Grant²,

Gorelick³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Aberrant cytosolic Ca2+ flux in pancreatic acinar cells is critical to the pathological pancreatic zymogen activation observed in acute pancreatitis, but the downstream effectors are not known. In this study, we examined the role of Ca2+-activated protein phosphatase 2B (or calcineurin) in zymogen activation. Isolated pancreatic acinar cells were stimulated with supraphysiological caerulein (100 nM) with or without the calcineurin inhibitors FK506 or cell-permeable calcineurin inhibitory peptide (CiP). Chymotrypsin activity was measured as a marker of zymogen activation, and the percent amylase secretion was used as a measure of enzyme secretion. Cytosolic Ca2+ changes were recorded in acinar cells loaded with the intermediate Ca2+-affinity dye fluo-5F using a scanning confocal microscope. A 50% reduction in chymotrypsin activity was observed after pretreatment with 1 μM FK506 or 10 μM CiP. These pretreatments did not affect amylase secretion or the rise in cytosolic Ca2+ after caerulein stimulation. These findings suggest that calcineurin mediates caerulein-induced intra-acinar zymogen activation but not enzyme secretion or the initial caerulein-induced cytosolic Ca2+ signal.

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Section: Chymotrypsin Activation Is Dependent On a Rise In Ca Imentioning

confidence: 60%

Section: Chymotrypsin Activation Is Dependent On a Rise In Ca Imentioning

confidence: 99%

Caerulein-induced intracellular pancreatic zymogen activation is dependent on calcineurin

Husain¹,

Grant²,

Gorelick³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…3 D and E), and positive control experiments verified their effectiveness for blocking capsaicin-induced tachyphylaxis. The involvement of the calcineurin pathway was confirmed in skin superfusion assay by using a cell permeable CAIP T (38) (Fig. 3F).…”

Section: Test) (E) Effectmentioning

confidence: 69%

The cannabinoid WIN 55,212-2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin

Patwardhan

Jeske

Price

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

146

111

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Cannabinoids can evoke antihyperalgesia and antinociception at a peripheral site of action. However, the signaling pathways mediating these effects are not clearly understood. We tested the hypothesis that certain cannabinoids directly inhibit peripheral capsaicin-sensitive nociceptive neurons by dephosphorylating and desensitizing transient receptor potential vanilloid 1 (TRPV1) via a calcium calcineurin-dependent mechanism. Application of the cannabinoid WIN 55,212-2 (WIN) to cultured trigeminal (TG) neurons or isolated skin biopsies rapidly and significantly inhibited capsaicinactivated inward currents and neuropeptide exocytosis by a mechanism requiring the presence of extracellular calcium. The inhibitory effect did not involve activation of G protein-coupled cannabinoid receptors, because neither pertussis toxin nor GDP␤S treatments altered the WIN effect. However, application of WINactivated calcineurin, as measured by nuclear translocation of the nuclear factor of activated T cells (NFAT)c4 transcription factor, dephosphorylated TRPV1. The WIN-induced desensitization of TRPV1 was mediated by calcineurin, because the application of structurally distinct calcineurin antagonists (calcineurin autoinhibitory peptide and cyclosporine͞cyclophilin complex) abolished WINinduced inhibition of capsaicin-evoked inward currents and neuropeptide exocytosis. This mechanism also contributed to peripheral antinociceptive͞antihyperalgesic effects of WIN because pretreatment with the calcineurin antagonist calcineurin autoinhibitory peptide (CAIP) significantly reduced peripherally mediated WIN effects in two behavioral models. Collectively, these data demonstrate that cannabinoids such as WIN directly inhibit TRPV1 functional activities via a calcineurin pathway that represents a mechanism of cannabinoid actions at peripheral sites.lthough cannabinoids have been used to treat pain for millennia, the mechanisms of their actions are still not well understood. Cannabinoids activate numerous signaling pathways because they bind to both G protein-coupled receptors (GPCRs), such as CB1 and CB2, as well as ionotropic receptors, such as transient receptor potential vanilloid 1 (TRPV1), TRPV4, and TRPA1 (1-5). Spinal and supraspinal administration of cannabinoids leads to antihyperalgesia or antinociception in several acute and chronic pain models (6-8). Cannabinoids also evoke peripherally mediated antihyperalgesia or antinociception in several pain models (9-12). Although the CNS effects of cannabinoids on nociception appear to be mediated primarily by the CB1 cannabinoid receptor (13), the peripheral mechanisms of cannabinoid effects on nociceptive neurons appear to be indirect or possibly involve non-CB1 or -CB2 receptors because of the low level of expression of CB1 or CB2 receptors in nociceptive neurons (14-16).The thermal and capsaicin-sensitive TRPV1 channel plays a key role in thermal inflammatory hyperalgesia and neuropathic pain (17-19). TRPV1 channel activity is modulated by its phosphorylation status (17) and the pho...

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“…Heparin was purchased from Pfizer, the PP2B autoinhibitory peptide was obtained from Merck (21), and reversin 121 and verapamil were from Merck. Human apolipoprotein A-I (apoA-I), low density lipoprotein (LDL), acetylated LDL (AcLDL), and lipoprotein-deficient serum were prepared as described (22).…”

Section: Methodsmentioning

confidence: 99%

Cyclosporin A Decreases Apolipoprotein E Secretion from Human Macrophages via a Protein Phosphatase 2B-dependent and ATP-binding Cassette Transporter A1 (ABCA1)-independent Pathway

Kockx

Guo

Traini

et al. 2009

Journal of Biological Chemistry

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Cyclosporin A (CsA) is an immunosuppressant that inhibits protein phosphatase 2B (PP2B/calcineurin) and is associated with hyperlipidemia, decreased cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1), and increased risk of atherosclerosis. Apolipoprotein E (apoE) is an important regulator of lipid metabolism and atherosclerosis, the secretion of which from human macrophages is regulated by the serine/threonine protein kinase A (PKA) and intracellular calcium (Ca 2؉ ) (Kockx, M., Guo, D. L., Huby, T., Lesnik, P., Kay, J., Sabaretnam, T., Jary, E., Hill, M., Gaus, K., Chapman, J., Stow, J. L., Jessup, W., and Kritharides, L. (2007) Circ. Res. 101, 607-616). As PP2B is Ca 2؉ -dependent and has been linked to PKA-dependent processes, we investigated whether CsA modulated apoE secretion. CsA dose-and time-dependently inhibited secretion of apoE from primary human macrophages and from Chinese hamster ovary cells stably transfected with human apoE and increased cellular apoE levels without affecting apoE mRNA. [ 35 S]Met kinetic modeling studies showed that CsA inhibited both secretion and degradation of apoE, increasing the half-life of cellular apoE 2-fold. CsA also inhibited secretion from primary human Tangier disease macrophages and from mouse macrophages deficient in ABCA1, indicating that the effect is independent of the known inhibition of ABCA1 by CsA. The role of PP2B in mediating apoE secretion was confirmed using additional peptide and chemical inhibitors of PP2B. Importantly, kinetic modeling, live-cell imaging, and confocal microscopy all indicated that CsA inhibited apoE secretion by mechanisms quite distinct from those of PKA inhibition, most likely inducing accumulation of apoE in the endoplasmic reticulum compartment. Taken together,theseresultsestablishanovelmechanismforthepro-atherosclerotic effects of CsA, and establish for the first time a role for PP2B in regulating the intracellular transport and secretion of apoE.2 is a commonly administered immunosuppressant drug used in organ transplant recipients and in patients with autoimmune disorders. Its immunosuppressive activity is mediated by inhibition of protein phosphatase 2B (PP2B), also known as calcineurin. CsA binds to its intracellular receptor cyclophilin, and the CsA-cyclophilin complex binds PP2B and inhibits its activity. This results in complete inhibition of the translocation of nuclear factor of activated T cells to the nucleus, suppressing the transcription of inflammatory genes (1).Although effective as an immunosuppressive agent, CsA has been shown to cause hyperlipidemia, hypertension, and diabetes, and long term treatment with CsA is associated with an increased risk of cardiovascular disease-related morbidity and mortality (2). The potential mechanisms underlying these adverse cardiovascular effects are diverse. CsA increases cholesteryl ester transfer protein activity, stimulates the susceptibility of low density lipoprotein (LDL) oxidation, decreases bile acid synthesis and biliary cholesterol excretion, reduces...

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Inhibition of excitatory neuronal cell death by cell‐permeable calcineurin autoinhibitory peptide

Cited by 34 publications

References 37 publications

Caerulein-induced intracellular pancreatic zymogen activation is dependent on calcineurin

Caerulein-induced intracellular pancreatic zymogen activation is dependent on calcineurin

The cannabinoid WIN 55,212-2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin

Cyclosporin A Decreases Apolipoprotein E Secretion from Human Macrophages via a Protein Phosphatase 2B-dependent and ATP-binding Cassette Transporter A1 (ABCA1)-independent Pathway

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