Increased intracellular Ca2+ concentrations prevent membrane localization of PH domains through the formation of Ca2+-phosphoinositides
- Authors
- Kang, Jin Ku; Kim, Ok-Hee; Hur, June; Yu, So Hee; Lamichhane, Santosh; Lee, Jin Wook; Ojha, Uttam; Hong, Jeong Hee; Lee, Cheol Soon; Cha, Ji-Young; Lee, Young Jae; Lm, Seung-Soon; Park, Young Joo; Choi, Cheol Soo; Lee, Dae Ho; Lee, In-Kyu; Oh, Byung-Chul
- Issue Date
- 7-Nov-2017
- Publisher
- NATL ACAD SCIENCES
- Keywords
- membrane localization; PH domain; Ca2+-phosphoinositides; intracellular Ca2+ concentration; insulin resistance
- Citation
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.114, no.45, pp.11926 - 11931
- Journal Title
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
- Volume
- 114
- Number
- 45
- Start Page
- 11926
- End Page
- 11931
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/5467
- DOI
- 10.1073/pnas.1706489114
- ISSN
- 0027-8424
- 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.
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Collections - 의과대학 > 의학과 > 1. Journal Articles
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