Immunosuppressant calcineurin inhibitors phase shift circadian rhythms and inhibit circadian responses to light

Katz, Marcelo E.; Simonetta, Sergio Hernan; Ralph, Martin R.; Golombék, Diego A.

doi:10.1016/j.pbb.2008.05.017

Cited by 11 publications

(17 citation statements)

References 39 publications

(46 reference statements)

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“…Calcineurin is known to be involved in circadian phase-shifting in mammals (Katz et al, 2008), but it is not clear whether calcineurin itself is expressed in circadian oscillations. We first examined whether the protein expression or the activity of calcineurin was under circadian control.…”

Section: Resultsmentioning

confidence: 99%

“…Since calcineurin is known to cause circadian phase shifting in mammals (Katz et al, 2008), it is possible that the circadian phase-dependent regulation of L-VGCCs by calcineurin could be due to phase-shifting, in which L-VGCCα1 subunit mRNA would be affected after calcineurin inhibitor treatments. However, we found that while FK-506 dampened the circadian rhythm of L-VGCCα1D protein expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Calcineurin is also involved in circadian phase-shifting in mammals, since in vivo administration of calcineurin inhibitors blocks circadian responses to light at night, produces circadian phase advances when applied during the subjective day, and disrupts circadian locomotor behavior rhythms when applied chronically in hamsters (Katz et al, 2008). These effects of calcineurin inhibitors on circadian phase-shifting are in part attributed to their interference with intracellular Ca 2+ storage and release in SCN neurons (Ding et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…FK-506 and cyclosporine A inhibit calcineurin through interactions with FK-506 binding protein 12 (FKBP12) and cyclophilin A, respectively (Liu et al, 1991). Inhibition of calcineurin causes circadian phase shifts in mammals, which indicates that calcineurin is involved in the circadian input pathway to reset or entrain the circadian clock in the suprachiasmatic nucleus (SCN; Ding et al, 1998; Katz et al, 2008). In addition, other ser/thr phosphatase families, such as PP2A and PP1, are known to directly regulate the circadian clock mechanism in Drosophila and Neurospora (Sathyanarayanan et al, 2004; Yang et al, 2004; Schafmeier et al, 2005; Fang et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Calcineurin serves in the circadian output pathway to regulate the daily rhythm of L‐type voltage‐gated calcium channels in the retina

Huang

Vernikovskaya

et al. 2012

J of Cellular Biochemistry

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The L-type voltage-gated calcium channels (L-VGCCs) in avian retinal cone photoreceptors are under circadian control, in which the protein expression of the α1 subunits and the current density are greater at night than during the day. Both Ras-mitogen-activated protein kinase (MAPK) and Ras-phosphatidylionositol 3 kinase-protein kinase B (PI3K-AKT) signaling pathways are part of the circadian output that regulate the L-VGCC rhythm, while cAMP-dependent signaling is further upstream of Ras to regulate the circadian outputs in photoreceptors. However, there are missing links between cAMP-dependent signaling and Ras in the circadian output regulation of L-VGCCs. In this study, we report that calcineurin, a Ca2+/calmodulin-dependent serine (ser)/threonine (thr) phosphatase, participates in the circadian output pathway to regulate L-VGCCs through modulating both Ras-MAPK and Ras-PI3K-AKT signaling. The activity of calcineurin, but not its protein expression, was under circadian regulation. Application of a calcineurin inhibitor, FK-506 or cyclosporine A, reduced the L-VGCC current density at night with a corresponding decrease in L-VGCCα1D protein expression, but the circadian rhythm of L-VGCCα1D mRNA levels were not affected. Inhibition of calcineurin further reduced the phosphorylation of ERK and AKT (at thr 308) and inhibited the activation of Ras, but inhibitors of MAPK or PI3K signaling did not affect the circadian rhythm of calcineurin activity. However, inhibition of adenylate cyclase significantly dampened the circadian rhythm of calcineurin activity. These results suggest that calcineurin is upstream of MAPK and PI3K-AKT but downstream of cAMP in the circadian regulation of L-VGCCs.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Calcineurin serves in the circadian output pathway to regulate the daily rhythm of L‐type voltage‐gated calcium channels in the retina

Huang

Vernikovskaya

et al. 2012

J of Cellular Biochemistry

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“…Interestingly, we found that a number of cyclophilins that are active on the BMAL1 TAD are also expressed in vivo on a circadian timescale, suggesting the possibility for modes of feedback regulation that are common in circadian rhythms (Baggs et al, 2009). These findings are strengthened by the observation that animals with chronic administration of peptidyl-prolyl isomerases inhibitors exhibit defects in circadian cycling (Katz et al, 2008), as do organ transplant patients on long-term dosing of CsA (Kooman et al, 2001; van de Borne et al, 1993; van den Dorpel et al, 1996). More work is needed to parse out the potentially redundant roles of cyclophilins and possibly other proline isomerases on the BMAL1 TAD.…”

Section: Discussionmentioning

confidence: 97%

A Slow Conformational Switch in the BMAL1 Transactivation Domain Modulates Circadian Rhythms

et al. 2017

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SUMMARY The C-terminal transactivation domain (TAD) of BMAL1 (Brain and muscle ARNT-like 1) is a regulatory hub for transcriptional coactivators and repressors that compete for binding and consequently contributes to period determination of the mammalian circadian clock. Here, we report the discovery of two distinct conformational states that slowly exchange within the dynamic TAD to control timing. This binary switch results from cis/trans isomerization about a highly conserved Trp-Pro imide bond in a region of the TAD that is required for normal circadian timekeeping. Both cis and trans isomers interact with transcriptional regulators, suggesting that isomerization could serve a role in assembling regulatory complexes in vivo. Towards this end, we show that locking the switch into the trans isomer leads to shortened circadian periods. Furthermore, isomerization is regulated by the cyclophilin family of peptidyl-prolyl isomerases, highlighting the potential for regulation of BMAL1 protein dynamics in period determination.

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Sleep Patterns in Patients After Solid Organ Transplantation Including Gender and Age Differences. Survey Results From One Transplantation Centre in Poland

Olkowski,

Marczak,

Rostkowska

et al. 2024

Transplantation Proceedings

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Immunosuppressant calcineurin inhibitors phase shift circadian rhythms and inhibit circadian responses to light

Cited by 11 publications

References 39 publications

Calcineurin serves in the circadian output pathway to regulate the daily rhythm of L‐type voltage‐gated calcium channels in the retina

Calcineurin serves in the circadian output pathway to regulate the daily rhythm of L‐type voltage‐gated calcium channels in the retina

A Slow Conformational Switch in the BMAL1 Transactivation Domain Modulates Circadian Rhythms

Sleep Patterns in Patients After Solid Organ Transplantation Including Gender and Age Differences. Survey Results From One Transplantation Centre in Poland

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