Increased intracellular Ca2+ concentrations prevent membrane localization of PH domains through the formation of Ca2+-phosphoinositides
DC Field | Value | Language |
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dc.contributor.author | Kang, Jin Ku | - |
dc.contributor.author | Kim, Ok-Hee | - |
dc.contributor.author | Hur, June | - |
dc.contributor.author | Yu, So Hee | - |
dc.contributor.author | Lamichhane, Santosh | - |
dc.contributor.author | Lee, Jin Wook | - |
dc.contributor.author | Ojha, Uttam | - |
dc.contributor.author | Hong, Jeong Hee | - |
dc.contributor.author | Lee, Cheol Soon | - |
dc.contributor.author | Cha, Ji-Young | - |
dc.contributor.author | Lee, Young Jae | - |
dc.contributor.author | Lm, Seung-Soon | - |
dc.contributor.author | Park, Young Joo | - |
dc.contributor.author | Choi, Cheol Soo | - |
dc.contributor.author | Lee, Dae Ho | - |
dc.contributor.author | Lee, In-Kyu | - |
dc.contributor.author | Oh, Byung-Chul | - |
dc.date.available | 2020-02-27T16:42:35Z | - |
dc.date.created | 2020-02-06 | - |
dc.date.issued | 2017-11-07 | - |
dc.identifier.issn | 0027-8424 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/5467 | - |
dc.description.abstract | Insulin resistance, a key etiological factor in metabolic syndrome, is closely linked to ectopic lipid accumulation and increased intracellular Ca2+ concentrations in muscle and liver. However, the mechanism by which dysregulated intracellular Ca2+ homeostasis causes insulin resistance remains elusive. Here, we show that increased intracellular Ca2+ acts as a negative regulator of insulin signaling. Chronic intracellular Ca2+ overload in hepatocytes during obesity and hyperlipidemia attenuates the phosphorylation of protein kinase B (Akt) and its key downstream signaling molecules by inhibiting membrane localization of pleckstrin homology (PH) domains. Pharmacological approaches showed that elevated intracellular Ca2+ inhibits insulin-stimulated Akt phosphorylation and abrogates membrane localization of various PH domain proteins such as phospholipase C delta and insulin receptor substrate 1, suggesting a common mechanism inhibiting the membrane targeting of PH domains. PH domain-lipid overlay assays confirmed that Ca2+ abolishes the binding of various PH domains to phosphoinositides (PIPs) with two adjacent phosphate groups, such as PI(3,4)P-2, PI(4,5)P-2, and PI(3,4,5)P-3. Finally, thermodynamic analysis of the binding interaction showed that Ca2+-mediated inhibition of targeting PH domains to the membrane resulted from the tight binding of Ca2+ rather than PH domains to PIPs forming Ca2+-PIPs. Thus, Ca2+-PIPs prevent the recognition of PIPs by PH domains, potentially due to electrostatic repulsion between positively charged side chains in PH domains and the Ca2+-PIPs. Our findings provide a mechanistic link between intracellular Ca2+ dysregulation and Akt inactivation in insulin resistance. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | NATL ACAD SCIENCES | - |
dc.relation.isPartOf | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | - |
dc.subject | CALCIUM-CHANNEL BLOCKERS | - |
dc.subject | PLECKSTRIN HOMOLOGY DOMAINS | - |
dc.subject | BRUTONS TYROSINE KINASE | - |
dc.subject | BETA-PROPELLER PHYTASE | - |
dc.subject | INSULIN-RESISTANCE | - |
dc.subject | CYTOSOLIC CALCIUM | - |
dc.subject | LIPID-METABOLISM | - |
dc.subject | INDUCED OBESITY | - |
dc.subject | PALMITIC ACID | - |
dc.subject | BINDING | - |
dc.title | Increased intracellular Ca2+ concentrations prevent membrane localization of PH domains through the formation of Ca2+-phosphoinositides | - |
dc.type | Article | - |
dc.type.rims | ART | - |
dc.description.journalClass | 1 | - |
dc.identifier.wosid | 000414631200064 | - |
dc.identifier.doi | 10.1073/pnas.1706489114 | - |
dc.identifier.bibliographicCitation | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.114, no.45, pp.11926 - 11931 | - |
dc.identifier.scopusid | 2-s2.0-85033796172 | - |
dc.citation.endPage | 11931 | - |
dc.citation.startPage | 11926 | - |
dc.citation.title | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | - |
dc.citation.volume | 114 | - |
dc.citation.number | 45 | - |
dc.contributor.affiliatedAuthor | Kang, Jin Ku | - |
dc.contributor.affiliatedAuthor | Kim, Ok-Hee | - |
dc.contributor.affiliatedAuthor | Hur, June | - |
dc.contributor.affiliatedAuthor | Yu, So Hee | - |
dc.contributor.affiliatedAuthor | Lamichhane, Santosh | - |
dc.contributor.affiliatedAuthor | Lee, Jin Wook | - |
dc.contributor.affiliatedAuthor | Ojha, Uttam | - |
dc.contributor.affiliatedAuthor | Hong, Jeong Hee | - |
dc.contributor.affiliatedAuthor | Lee, Cheol Soon | - |
dc.contributor.affiliatedAuthor | Cha, Ji-Young | - |
dc.contributor.affiliatedAuthor | Lee, Young Jae | - |
dc.contributor.affiliatedAuthor | Choi, Cheol Soo | - |
dc.contributor.affiliatedAuthor | Lee, Dae Ho | - |
dc.contributor.affiliatedAuthor | Oh, Byung-Chul | - |
dc.type.docType | Article | - |
dc.subject.keywordAuthor | membrane localization | - |
dc.subject.keywordAuthor | PH domain | - |
dc.subject.keywordAuthor | Ca2+-phosphoinositides | - |
dc.subject.keywordAuthor | intracellular Ca2+ concentration | - |
dc.subject.keywordAuthor | insulin resistance | - |
dc.subject.keywordPlus | CALCIUM-CHANNEL BLOCKERS | - |
dc.subject.keywordPlus | PLECKSTRIN HOMOLOGY DOMAINS | - |
dc.subject.keywordPlus | BRUTONS TYROSINE KINASE | - |
dc.subject.keywordPlus | BETA-PROPELLER PHYTASE | - |
dc.subject.keywordPlus | INSULIN-RESISTANCE | - |
dc.subject.keywordPlus | CYTOSOLIC CALCIUM | - |
dc.subject.keywordPlus | LIPID-METABOLISM | - |
dc.subject.keywordPlus | INDUCED OBESITY | - |
dc.subject.keywordPlus | PALMITIC ACID | - |
dc.subject.keywordPlus | BINDING | - |
dc.relation.journalResearchArea | Science & Technology - Other Topics | - |
dc.relation.journalWebOfScienceCategory | Multidisciplinary Sciences | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
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