Effect of roscovitine on intracellular calcium dynamics: differential enantioselective responses.

Details

Serval ID
serval:BIB_3FD5895BB955
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Effect of roscovitine on intracellular calcium dynamics: differential enantioselective responses.
Journal
Molecular Pharmaceutics
Author(s)
Tamma G., Ranieri M., Di Mise A., Spirlì A., Russo A., Svelto M., Valenti G.
ISSN
1543-8392 (Electronic)
ISSN-L
1543-8384
Publication state
Published
Issued date
2013
Peer-reviewed
Oui
Volume
10
Number
12
Pages
4620-4628
Language
english
Notes
Publication types: Journal Article Publication Status: ppublish
Abstract
Cyclin-dependent kinases (CDKs) inhibitors have emerged as interesting therapeutic candidates. Of these, (S)-roscovitine has been proposed as potential neuroprotective molecule for stroke while (R)-roscovitine is currently entering phase II clinical trials against cancers and phase I clinical tests against glomerulonephritis. In addition, (R)-roscovitine has been suggested as potential antihypertensive and anti-inflammatory drug. Dysfunction of intracellular calcium balance is a common denominator of these diseases, and the two roscovitine enantiomers (S and R) are known to modulate calcium voltage channel activity differentially. Here, we provide a detailed description of short- and long-term responses of roscovitine on intracellular calcium handling in renal epithelial cells. Short-term exposure to (S)-roscovitine induced a cytosolic calcium peak, which was abolished after stores depletion with cyclopiazonic acid (CPA). Instead, (R)-roscovitine caused a calcium peak followed by a small calcium plateau. Cytosolic calcium response was prevented after stores depletion. Bafilomycin, a selective vacuolar H(+)-ATPase inhibitor, abolished the small calcium plateau. Long-term exposure to (R)-roscovitine significantly reduced the basal calcium level compared to control and (S)-roscovitine treated cells. However, both enantiomers increased calcium accumulation in the endoplasmic reticulum (ER). Consistently, cells treated with (R)-roscovitine showed a significant increase in SERCA activity, whereas (S)-roscovitine incubation resulted in a reduced PMCA expression. We also found a tonic decreased ability to release calcium from the ER, likely via IP3 signaling, under treatment with (S)- or (R)-roscovitine. Together our data revealed that (S)-roscovitine and (R)-roscovitine exert distinct enantiospecific effects on intracellular calcium signaling in renal epithelial cells. This distinct pharmacological profile can be relevant for roscovitine clinical use.
Pubmed
Web of science
Create date
03/01/2014 9:36
Last modification date
20/10/2020 10:08
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