scholarly journals Branches on the α-C Atom of Cyclosporin A Residue 3 Result in Direct Calcineurin Inhibition and Rapid Cyclophilin 18 Binding

ChemBioChem ◽  
2004 ◽  
Vol 5 (9) ◽  
pp. 1169-1169
Author(s):  
Yixin Zhang ◽  
Ria Baumgrass ◽  
Mike Schutkowski ◽  
Gunter Fischer
Keyword(s):  
Cyclosporin A ◽  
Calcineurin Inhibition

scholarly journals Comparative Neuroprotective Effects of Cyclosporin a and NIM811, a Nonimmunosuppressive Cyclosporin a Analog, following Traumatic Brain Injury

2008 ◽  
Vol 29 (1) ◽  
pp. 87-97 ◽  
Author(s):  
Lamin Han Mbye ◽  
Indrapal N Singh ◽  
Kimberly M Carrico ◽  
Kathryn E Saatman ◽  
Edward D Hall
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cyclosporin A ◽  
Mitochondrial Dysfunction ◽  
Motor Function ◽  
Neurological Dysfunction ◽  
Neuroprotective Effects ◽  
Function Impairment ◽  
Calcineurin Inhibition ◽  
Experimental Traumatic Brain Injury

Earlier experiments have shown that cyclosporin A (CsA) and its non-calcineurin inhibitory analog NIM811 attenuate mitochondrial dysfunction after experimental traumatic brain injury (TBI). Presently, we compared the neuroprotective effects of previously determined mitochondrial protective doses of CsA (20 mg/kg intraperitoneally) and NIM811 (10 mg/kg intraperitoneally) when administered at 15 mins postinjury in preventing cytoskeletal (α-spectrin) degradation, neuro-degeneration, and neurological dysfunction after severe (1.0 mm) controlled cortical impact (CCI) TBI in mice. In a first set of experiments, we analyzed calpain-mediated α-spectrin proteolysis at 24 h postinjury. Both NIM811 and CsA significantly attenuated the increased α-spectrin breakdown products observed in vehicle-treated animals ( P < 0.005). In a second set of experiments, treatment of animals with either NIM811 or CsA at 15 mins and again at 24 h postinjury attenuated motor function impairment at 48 h and 7 days ( P < 0.005) and neurodegeneration at 7 days postinjury ( P < 0.0001). Delayed administration of NIM811 out to 12 h was still able to significantly reduce α-spectrin degradation. These results show that the neuroprotective mechanism of CsA involves maintenance of mitochondrial integrity and that calcineurin inhibition plays little or no role because the non-calcineurin inhibitory analog, NIM811, is as effective as CsA.

Branches on the α-C Atom of Cyclosporin A Residue 3 Result in Direct Calcineurin Inhibition and Rapid Cyclophilin 18 Binding

ChemBioChem ◽  
2004 ◽  
Vol 5 (7) ◽  
pp. 1006-1009 ◽  
Author(s):  
Yixin Zhang ◽  
Ria Raumgrass ◽  
Mike Schutkowski ◽  
Gunter Fischer
Keyword(s):  
Cyclosporin A ◽  
Calcineurin Inhibition

scholarly journals Calcineurin is associated with the cytoskeleton of cultured neurons and has a role in the acquisition of polarity.

1993 ◽  
Vol 4 (12) ◽  
pp. 1225-1238 ◽  
Author(s):  
A Ferreira ◽  
R Kincaid ◽  
K S Kosik
Keyword(s):  
Cyclosporin A ◽  
Normal Development ◽  
Cultured Cells ◽  
Cell Types ◽  
Axonal Elongation ◽  
Neurite Elongation ◽  
Developing Neurons ◽  
Calcineurin Inhibition ◽  
Specific Peptide

Calcineurin is a calmodulin-dependent serine-threonine phosphatase found in many cell types but most abundant in neurons. To determine its localization in developing neurons, dissociated cultures from embryonic day 15 rat cerebellum were analyzed immunocytochemically after treatment with cytoskeletal-disrupting drugs. During the initial outgrowth of neurites, calcineurin is enriched in growth cones where its localization depends upon the integrity of both microtubules and actin filaments. Treatment with cytochalasin shifts calcineurin from the growth cone to the neurite shaft, and with nocadozole calcineurin translocates to the cell body. Therefore calcineurin is well positioned to mediate interactions between cytoskeletal systems during neurite elongation. By 14 d in culture, when the neurons have developed extensive neuronal contacts and synapses are present, calcineurin is predominantly in the neurite shaft. Incubation of cultured cells with Cyclosporin A or a specific peptide, both of which selectively inhibit calcineurin's phosphatase activity, prevented axonal elongation. Because the microtubule-associated protein tau appears to play a key role in asymmetric neurite elongation, we examined modifications in its phosphorylation state resulting from calcineurin inhibition. In contrast to the normal development of cerebellar macroneurons in which reactivity with the phosphorylation-dependent antibody, tau-1, progressively increases, there was a persistent inhibition of tau-1 reactivity in cells exposed to Cyclosporin A. These findings suggest a role for calcineurin in regulating tau phosphorylation and possibly modulating other steps required for the determination of polarity.

scholarly journals Active site mutants of human cyclophilin A separate peptidyl-prolyl isomerase activity from cyclosporin A binding and calcineurin inhibition

1992 ◽  
Vol 1 (9) ◽  
pp. 1092-1099 ◽  
Author(s):  
Lynne D. Zydowsky ◽  
Felicia A. Etzkorn ◽  
Howard Y. Chang ◽  
Stephen B. Ferguson ◽  
Lesley A. Stolz ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Active Site ◽  
Cyclophilin A ◽  
Prolyl Isomerase ◽  
Peptidyl Prolyl Isomerase ◽  
Isomerase Activity ◽  
Active Site Mutants ◽  
Calcineurin Inhibition

An emerging role for calcineurin Aα in the development and function of the kidney

2006 ◽  
Vol 290 (4) ◽  
pp. F769-F776 ◽  
Author(s):  
Jennifer L. Gooch
Keyword(s):  
T Cells ◽  
Cyclosporin A ◽  
Renal Dysfunction ◽  
Knockout Mice ◽  
Immunosuppressive Agents ◽  
Calcineurin Inhibitors ◽  
The Body ◽  
Developmental Defects ◽  
And Function ◽  
Calcineurin Inhibition

For many years, calcineurin has been a familiar molecule as a target of the immunosuppressive agents cyclosporin A and FK-506. Calcineurin inhibition interferes with T cell signaling by preventing activation of the transcription factor NFATc. However, calcineurin is expressed in most tissues in the body, and calcineurin inhibition undoubtedly alters many other cellular processes. As a result, serious side effects of calcineurin inhibitors regularly occur, including hypertension and renal dysfunction. Because nephrotoxicity is often a barrier to continued clinical use of calcineurin inhibitors, understanding the role of calcineurin in the kidney is of particular importance. Recent work has demonstrated that the two main isoforms of the catalytic subunit of calcineurin, Aα and Aβ, may have distinct functions, particularly in the kidney. Calcineurin isoforms may be differentially expressed, and/or the activity of each may be differentially regulated, leading to tissue-specific functions. Differences between the action of the two isoforms are most evident in knockout mice lacking each isoform. Mice lacking the β-isoform are characterized principally by altered development and function of immune cells. α-Knockout mice, in contrast, can still be immune suppressed by cyclosporin A but display pervasive developmental defects, including renal dysfunction. Therefore, it is intriguing to consider that while the β-isoform may be responsible for calcineurin action in T cells, the α-isoform may be the predominant catalytic isoform in the kidney. This conclusion, if correct, may have substantial clinical implication for novel strategies to selectively target calcineurin action in T cells without associated nephrotoxicity.

scholarly journals FKBP51, a novel T-cell-specific immunophilin capable of calcineurin inhibition.

1995 ◽  
Vol 15 (8) ◽  
pp. 4395-4402 ◽  
Author(s):  
G Baughman ◽  
G J Wiederrecht ◽  
N F Campbell ◽  
M M Martin ◽  
S Bourgeois
Keyword(s):  
T Cells ◽  
Cyclosporin A ◽  
Phosphatase Activity ◽  
Immunosuppressive Drugs ◽  
Drug Binding ◽  
Prolyl Isomerase ◽  
Peptidyl Prolyl Isomerase ◽  
Isomerase Activity ◽  
Calcineurin Phosphatase ◽  
Calcineurin Inhibition

The immunosuppressive drugs FK506 and cyclosporin A block T-lymphocyte proliferation by inhibiting calcineurin, a critical signaling molecule for activation. Multiple intracellular receptors (immunophilins) for these drugs that specifically bind either FK506 and rapamycin (FK506-binding proteins [FKBPs]) or cyclosporin A (cyclophilins) have been identified. We report the cloning and characterization of a new 51-kDa member of the FKBP family from murine T cells. The novel immunophilin, FKBP51, is distinct from the previously isolated and sequenced 52-kDa murine FKBP, demonstrating 53% identity overall. Importantly, Western blot (immunoblot) analysis showed that unlike all other FKBPs characterized to date, FKBP51 expression was largely restricted to T cells. Drug binding to recombinant FKBP51 was demonstrated by inhibition of peptidyl prolyl isomerase activity. As judged from peptidyl prolyl isomerase activity, FKBP51 had a slightly higher affinity for rapamycin than for FK520, an FK506 analog. FKBP51, when complexed with FK520, was capable of inhibiting calcineurin phosphatase activity in an in vitro assay system. Inhibition of calcineurin phosphatase activity has been implicated both in the mechanism of immunosuppression and in the observed toxic side effects of FK506 in nonlymphoid cells. Identification of a new FKBP that can mediate calcineurin inhibition and is restricted in its expression to T cells suggests that new immunosuppressive drugs may be identified that, by virtue of their specific interaction with FKBP51, would be targeted in their site of action.

scholarly journals Impact of Cyclosporin A Pharmacokinetics on the Presence of Side Effects in Pediatric Renal Transplantation

2000 ◽  
Vol 11 (2) ◽  
pp. 343-349
Author(s):  
ELIAS DAVID-NETO ◽  
FRANCINE BRAMBATE CARVALHINHO LEMOS ◽  
ERIKA ARAI FURUSAWA ◽  
BENITA SOARES SCHWARTZMAN ◽  
JULIANA SOARES CAVALCANTE ◽  
...  
Keyword(s):  
Renal Transplantation ◽  
Side Effects ◽  
Cyclosporin A ◽  
Area Under The Curve ◽  
Gingival Hyperplasia ◽  
Morning Dose ◽  
Pediatric Renal Transplantation ◽  
Blood Concentrations ◽  
Calcineurin Inhibition ◽  
Cutoff Levels

Cyclosporin A (CsA) is a potent immunosuppressant that has many side effects, including hypertrichosis, gingival hyperplasia, and tremor. To evaluate whether there is a relationship between the CsA-pharmacokinetics (PK) and these side effects, their presence and intensity were observed in 46 renal transplanted children/adolescents during two regular visits, and the occurrence of the side effects was correlated with CsA-PK. CsA doses had been unchanged for at least 6 mo. CsA blood concentrations were measured at time 0, and 1, 2, and 4 h after the CsA morning dose. An abbreviated area under the curve (AUC) was calculated using C0, C2, and C4. Hypertrichosis positively correlated with C2, C4, Cmax, and AUC. An AUC ≥ 4158 ng/ml per h was the best predictor for the presence of hypertrichosis. Tremor was also positively correlated with C2, Cmax, and AUC. A Cmax ≥ 878 ng/ml was the best predictor for the appearance of tremor. These values of Cmax and AUC are within the therapeutic range of CsA as demonstrated by the studies of calcineurin inhibition by CsA. Gingival hyperplasia was not associated with any of the CsA-PK studied parameters. However, it was associated with the concomitant use of nifedipine. These data show that there is a correlation between the CsA side effects and its pharmacokinetics and that it is possible to decrease the incidence and intensity of such side effects by monitoring the CsA-PK parameters, providing they are under or at the proposed cutoff levels. Nifedipine should also be avoided to reduce the presence of gingival hyperplasia.

scholarly journals Independent inhibition of calcineurin and K+ currents by the immunosuppressant FK-506 in rat ventricle

1998 ◽  
Vol 275 (6) ◽  
pp. H2041-H2052 ◽  
Author(s):  
W. H. duBell ◽  
S. T. Gaa ◽  
W. J. Lederer ◽  
T. B. Rogers
Keyword(s):  
Action Potential ◽  
Cyclosporin A ◽  
Ventricular Myocytes ◽  
Fk 506 ◽  
Rat Ventricle ◽  
Physiological And Biochemical ◽  
Calcineurin Activity ◽  
Calcineurin Inhibition ◽  
K Currents

FK-506 increases the cytosolic Ca2+ concentration transient in rat ventricular myocytes by prolonging the action potential through inhibition of the K+ currents I to and I K[ J. Physiol. (Lond.) 501: 509–516, 1997]. Physiological and biochemical techniques were used in parallel to examine the electrophysiological mechanisms and the role of calcineurin inhibition in these effects. FK-506 prolonged the recovery of I to from inactivation. Thus I to inhibition was frequency dependent, with no decrease at 0.2 Hz (recorded at +50 mV from −70 mV) but a 40% decrease at 2.0 Hz. In contrast, inhibition of I K(∼60%) was time and voltage independent. At 25 μM, FK-506 (by 65%) and cyclosporin A (by 57%) inhibited calcineurin activity in myocyte extracts. However, only FK-506 increased the cytosolic Ca2+ concentration transient in field-stimulated myocytes. Furthermore, FK-506 was still active on K+ currents when cells were dialyzed with 10 mM EGTA. These results demonstrate that calcineurin inhibition is not responsible for the functional effects of FK-506 in heart and suggest that I K and I to are modulated by FK-506-binding proteins or directly by FK-506.

Sign in / Sign up

Export Citation Format

Share Document