Calcium signaling mediated by aminergic GPCRs is impaired by the PI3K inhibitor LY294002 and its analog LY303511 in a PI3K-independent manner

The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 (LY294) and its much less active analog LY303511 (LY303) constitute the paired probe that is commonly used to demonstrate the involvement of PI3K in intracellular signaling. We studied effects of LY294 and LY303 on Ca2+ signaling initiated by c...

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Published in:European journal of pharmacology 2020-08, Vol.880, p.173182-173182, Article 173182
Main Authors: Kotova, Polina D., Kochkina, Ekaterina N., Lyamin, Oleg O., Rogachevskaja, Olga A., Korolenko, Nina P., Ivashin, Denis S., Bystrova, Marina F., Enukashvily, Natella I., Kolesnikov, Stanislav S.
Format: Article
Language:English
Subjects:
Acetylcholine - pharmacology
Adenosine Triphosphate - pharmacology
Aminergic GPCR
Animals
Ca2+ signaling
Calcium Signaling - drug effects
Cells, Cultured
Chromones - pharmacology
Cricetulus
Histamine - pharmacology
Humans
LY294002
LY303511
Mesenchymal Stem Cells - drug effects
Mesenchymal Stem Cells - metabolism
Mesenchymal stromal cells
Morpholines - pharmacology
Phosphoinositide-3 Kinase Inhibitors - pharmacology
PI3 kinase
Piperazines - pharmacology
Serotonin - pharmacology
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Summary:The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 (LY294) and its much less active analog LY303511 (LY303) constitute the paired probe that is commonly used to demonstrate the involvement of PI3K in intracellular signaling. We studied effects of LY294 and LY303 on Ca2+ signaling initiated by certain GPCR agonists in cells of several lines, including CHO cells expressing the recombinant serotonin receptor 5-HT2C and mesenchymal stromal cells derived from the human adipose tissue (AD-MSCs) and umbilical cord (UD-MSCs). The LY294/LY303 pair exerted apparently specific effects on responsiveness of AD-MSCs to ATP, suggesting the involvement of PI3K in ATP transduction. Surprisingly, LY303 inhibited Ca2+ transients elicited by histamine in the same cells, while LY294 was ineffective. This observation and other findings implicated a PI3K-unrelated mechanism in mediating effects of the LY compound on AD-MSC responsiveness to histamine. With LY303 in the bath, the dose dependence of histamine responses was shifted positively at the invariable number of responsive cells, as would be the case with a competitive antagonist of histamine receptors. Moreover, LY303 and LY294 inhibited Ca2+ transients elicited by acetylcholine and serotonin in UD-MSCs and CHO/5-HT2C cells, respectively. Our overall results argued for the possibility that LY294 and LY303 could directly affect activity of aminergic GPCRs. Thus, LY303511 and LY294002 should be used cautiously in studies of PI3K as a factor of GPCR signaling.
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2020.173182