Fingolimod (FTY720) stimulates Ca2+/calcineurin signaling in fission yeast

Kanako Hagihara, Ayako Kita, Aya Mizukura, Mariko Yao, Yuki Kitai, Tatsuki Kunoh, Takashi Masuko, Sumio Matzno, Kenji Chiba, Reiko Sugiura

Research output: Contribution to journalArticle

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Abstract

Fingolimod hydrochloride (FTY720) is the first in class of sphingosine 1-phosphate (S1P) receptor modulator approved to treat multiple sclerosis via down-regulation of G protein-coupled S1P receptor 1 by its phosphorylated form (FTY720-P). Many studies have revealed that FTY720 exerts various biological effects, including antitumor activities, angiogenesis inhibition, Ca 2+ mobilization and apoptosis, independently of S1P receptors. However, the exact mechanisms underlying their effects or signaling pathways mediated by FTY720 have not been completely established. To gain further insights into molecular mechanisms of FTY720 action, the effect of FTY720 on Ca2+ signaling in fission yeast was analyzed. The addition of Ca 2+ enhanced the sensitivity induced by FTY720, and mutants lacking genes required for calcium homeostasis, including calcineurin and its downstream transcription factor, Ppb1-responsive zinc finger protein (Prz1), were hypersensitive to FTY720 and CaCl2. The effect of FTY720 on calcineurin signaling was monitored by utilizing a luciferase reporter construct fused to three tandem repeats of the calcineurin-dependent response element (CDRE), which gives an accurate measure of calcineurin activity. The addition of FTY720 increased calcineurin activity as well as Ca2+ influx in a concentration-dependent manner. Notably, the FTY720-mediated Ca2+ influx and calcineurin activation were reduced markedly by the deletion of yam8+ or cch1+ encoding putative subunits of a Ca 2+ channel. Consistently, the deletion of Pmk1 mitogen-activated protein kinase (MAPK), which plays an important role in the activation of the Yam8/Cch1 channel, markedly decreased the intracellular Ca2+ levels upon FTY720 treatment. These results suggest that the FTY720-stimulated Ca 2+/calcineurin signaling activation partly involves the Yam8/Cch1 channel in fission yeast.

Original languageEnglish
Article numbere81907
JournalPLoS One
Volume8
Issue number12
DOIs
Publication statusPublished - Dec 3 2013
Externally publishedYes

Fingerprint

Schizosaccharomyces
Calcineurin
Schizosaccharomyces pombe
Yeast
sphingosine
calcium
phosphates
receptors
Lysosphingolipid Receptors
tandem repeat sequences
response elements
zinc finger motif
sclerosis
luciferase
angiogenesis
G-proteins
mitogen-activated protein kinase
Chemical activation
mechanism of action
homeostasis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Hagihara, K., Kita, A., Mizukura, A., Yao, M., Kitai, Y., Kunoh, T., ... Sugiura, R. (2013). Fingolimod (FTY720) stimulates Ca2+/calcineurin signaling in fission yeast. PLoS One, 8(12), [e81907]. https://doi.org/10.1371/journal.pone.0081907

Fingolimod (FTY720) stimulates Ca2+/calcineurin signaling in fission yeast. / Hagihara, Kanako; Kita, Ayako; Mizukura, Aya; Yao, Mariko; Kitai, Yuki; Kunoh, Tatsuki; Masuko, Takashi; Matzno, Sumio; Chiba, Kenji; Sugiura, Reiko.

In: PLoS One, Vol. 8, No. 12, e81907, 03.12.2013.

Research output: Contribution to journalArticle

Hagihara, K, Kita, A, Mizukura, A, Yao, M, Kitai, Y, Kunoh, T, Masuko, T, Matzno, S, Chiba, K & Sugiura, R 2013, 'Fingolimod (FTY720) stimulates Ca2+/calcineurin signaling in fission yeast', PLoS One, vol. 8, no. 12, e81907. https://doi.org/10.1371/journal.pone.0081907
Hagihara K, Kita A, Mizukura A, Yao M, Kitai Y, Kunoh T et al. Fingolimod (FTY720) stimulates Ca2+/calcineurin signaling in fission yeast. PLoS One. 2013 Dec 3;8(12). e81907. https://doi.org/10.1371/journal.pone.0081907
Hagihara, Kanako ; Kita, Ayako ; Mizukura, Aya ; Yao, Mariko ; Kitai, Yuki ; Kunoh, Tatsuki ; Masuko, Takashi ; Matzno, Sumio ; Chiba, Kenji ; Sugiura, Reiko. / Fingolimod (FTY720) stimulates Ca2+/calcineurin signaling in fission yeast. In: PLoS One. 2013 ; Vol. 8, No. 12.
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