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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| Veröffentlicht in: | European journal of pharmacology 2020-08, Vol.880, p.173182-173182, Article 173182 |
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| creator | 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. |
| description | 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. |
| doi_str_mv | 10.1016/j.ejphar.2020.173182 |
| format | Article |
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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.</description><identifier>ISSN: 0014-2999</identifier><identifier>EISSN: 1879-0712</identifier><identifier>DOI: 10.1016/j.ejphar.2020.173182</identifier><identifier>PMID: 32416185</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>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</subject><ispartof>European journal of pharmacology, 2020-08, Vol.880, p.173182-173182, Article 173182</ispartof><rights>2020 Elsevier B.V.</rights><rights>Copyright © 2020 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-b0e03d3aabec73ea860d8b6c9dc19af68da0b33f74d09ee0ff08bd55b558d5583</citedby><cites>FETCH-LOGICAL-c362t-b0e03d3aabec73ea860d8b6c9dc19af68da0b33f74d09ee0ff08bd55b558d5583</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0014299920302740$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32416185$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kotova, Polina D.</creatorcontrib><creatorcontrib>Kochkina, Ekaterina N.</creatorcontrib><creatorcontrib>Lyamin, Oleg O.</creatorcontrib><creatorcontrib>Rogachevskaja, Olga A.</creatorcontrib><creatorcontrib>Korolenko, Nina P.</creatorcontrib><creatorcontrib>Ivashin, Denis S.</creatorcontrib><creatorcontrib>Bystrova, Marina F.</creatorcontrib><creatorcontrib>Enukashvily, Natella I.</creatorcontrib><creatorcontrib>Kolesnikov, Stanislav S.</creatorcontrib><title>Calcium signaling mediated by aminergic GPCRs is impaired by the PI3K inhibitor LY294002 and its analog LY303511 in a PI3K-independent manner</title><title>European journal of pharmacology</title><addtitle>Eur J Pharmacol</addtitle><description>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.</description><subject>Acetylcholine - pharmacology</subject><subject>Adenosine Triphosphate - pharmacology</subject><subject>Aminergic GPCR</subject><subject>Animals</subject><subject>Ca2+ signaling</subject><subject>Calcium Signaling - drug effects</subject><subject>Cells, Cultured</subject><subject>Chromones - pharmacology</subject><subject>Cricetulus</subject><subject>Histamine - pharmacology</subject><subject>Humans</subject><subject>LY294002</subject><subject>LY303511</subject><subject>Mesenchymal Stem Cells - drug effects</subject><subject>Mesenchymal Stem Cells - metabolism</subject><subject>Mesenchymal stromal cells</subject><subject>Morpholines - pharmacology</subject><subject>Phosphoinositide-3 Kinase Inhibitors - pharmacology</subject><subject>PI3 kinase</subject><subject>Piperazines - pharmacology</subject><subject>Serotonin - pharmacology</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UcGOFCEUJEbjjqt_YAxHLz0-oOmGi4mZ6LrZSdwYPXgiNLyeYdJNt9Bjsh_hP8turx4NhEoeVVSoIuQ1gy0D1rw7bfE0H23acuBl1Aqm-BOyYarVFbSMPyUbAFZXXGt9QV7kfAIAqbl8Ti4Er1nDlNyQ3zs7uHAeaQ6HaIcQD3REH-yCnnZ31I4hYjoER69ud18zDWWPsw1pvV6OSG-vxQ0N8Ri6sEyJ7n9wXQNwaqOnYckF7TAdylyAkIwVKrUPoipEjzOWIy50tLEYvSTPejtkfPWIl-T7p4_fdp-r_Zer692HfeVEw5eqAwThhbUdulagVQ141TVOe8e07RvlLXRC9G3tQSNC34PqvJSdlKqAEpfk7frunKafZ8yLGUN2OAw24nTOhtdQFquVLNR6pbo05ZywN3MKo013hoG5L8KczFqEuS_CrEUU2ZtHh3NXAv0n-pt8IbxfCVj--StgMtkFjK6En9Atxk_h_w5_AOhSmdw</recordid><startdate>20200805</startdate><enddate>20200805</enddate><creator>Kotova, Polina D.</creator><creator>Kochkina, Ekaterina N.</creator><creator>Lyamin, Oleg O.</creator><creator>Rogachevskaja, Olga A.</creator><creator>Korolenko, Nina P.</creator><creator>Ivashin, Denis S.</creator><creator>Bystrova, Marina F.</creator><creator>Enukashvily, Natella I.</creator><creator>Kolesnikov, Stanislav S.</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20200805</creationdate><title>Calcium signaling mediated by aminergic GPCRs is impaired by the PI3K inhibitor LY294002 and its analog LY303511 in a PI3K-independent manner</title><author>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.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-b0e03d3aabec73ea860d8b6c9dc19af68da0b33f74d09ee0ff08bd55b558d5583</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Acetylcholine - pharmacology</topic><topic>Adenosine Triphosphate - pharmacology</topic><topic>Aminergic GPCR</topic><topic>Animals</topic><topic>Ca2+ signaling</topic><topic>Calcium Signaling - drug effects</topic><topic>Cells, Cultured</topic><topic>Chromones - pharmacology</topic><topic>Cricetulus</topic><topic>Histamine - pharmacology</topic><topic>Humans</topic><topic>LY294002</topic><topic>LY303511</topic><topic>Mesenchymal Stem Cells - drug effects</topic><topic>Mesenchymal Stem Cells - metabolism</topic><topic>Mesenchymal stromal cells</topic><topic>Morpholines - pharmacology</topic><topic>Phosphoinositide-3 Kinase Inhibitors - pharmacology</topic><topic>PI3 kinase</topic><topic>Piperazines - pharmacology</topic><topic>Serotonin - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kotova, Polina D.</creatorcontrib><creatorcontrib>Kochkina, Ekaterina N.</creatorcontrib><creatorcontrib>Lyamin, Oleg O.</creatorcontrib><creatorcontrib>Rogachevskaja, Olga A.</creatorcontrib><creatorcontrib>Korolenko, Nina P.</creatorcontrib><creatorcontrib>Ivashin, Denis S.</creatorcontrib><creatorcontrib>Bystrova, Marina F.</creatorcontrib><creatorcontrib>Enukashvily, Natella I.</creatorcontrib><creatorcontrib>Kolesnikov, Stanislav S.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kotova, Polina D.</au><au>Kochkina, Ekaterina N.</au><au>Lyamin, Oleg O.</au><au>Rogachevskaja, Olga A.</au><au>Korolenko, Nina P.</au><au>Ivashin, Denis S.</au><au>Bystrova, Marina F.</au><au>Enukashvily, Natella I.</au><au>Kolesnikov, Stanislav S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Calcium signaling mediated by aminergic GPCRs is impaired by the PI3K inhibitor LY294002 and its analog LY303511 in a PI3K-independent manner</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>2020-08-05</date><risdate>2020</risdate><volume>880</volume><spage>173182</spage><epage>173182</epage><pages>173182-173182</pages><artnum>173182</artnum><issn>0014-2999</issn><eissn>1879-0712</eissn><abstract>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.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>32416185</pmid><doi>10.1016/j.ejphar.2020.173182</doi><tpages>1</tpages></addata></record> |
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| 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 |
| title | Calcium signaling mediated by aminergic GPCRs is impaired by the PI3K inhibitor LY294002 and its analog LY303511 in a PI3K-independent manner |
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