Increased intracellular Ca2+ concentrations prevent membrane localization of PH domains through the formation of Ca2+ -phosphoinositides

Proceedings of the National Academy of Sciences of the United States of America
Jin Ku KangByung-Chul Oh

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 Cδ 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)P2, PI(4,5)P2, and PI(3,4,5)P3 Finally, thermodynamic analysis of the binding interaction sho...Continue Reading

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Citations

Jul 20, 2018·Frontiers in Medicine·Nuria Oliva-VilarnauVolker M Lauschke
Jul 8, 2020·Proceedings of the National Academy of Sciences of the United States of America·Lien D NguyenBarbara E Ehrlich
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May 6, 2021·Physiological Reviews·Jun RenYingmei Zhang

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Methods Mentioned

BETA
confocal microscopy
Fluorescence
PMA
isothermal titration calorimetry

Software Mentioned

ImageJ

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