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• W2912141728 endingPage "375" @default.
• W2912141728 startingPage "361" @default.
• W2912141728 abstract "Guanine nucleotide-binding proteins (G proteins) facilitate the transduction of external signals to the cell interior, regulate most eukaryotic signaling, and thus have become crucial disease drivers. G proteins largely function at the inner leaflet of the plasma membrane (PM) using covalently attached lipid anchors. Both small monomeric and heterotrimeric G proteins are primarily prenylated, either with a 15-carbon farnesyl or a 20-carbon geranylgeranyl polyunsaturated lipid. The mevalonate [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase] pathway synthesizes lipids for G-protein prenylation. It is also the source of the precursor lipids for many biomolecules, including cholesterol. Consequently, the rate-limiting enzymes of the mevalonate pathway are major targets for cholesterol-lowering medications and anticancer drug development. Although prenylated G protein <i>γ</i> (G<i>γ</i>) is essential for G protein–coupled receptor (GPCR)-mediated signaling, how mevalonate pathway inhibitors, statins, influence subcellular distribution of G<i>βγ</i> dimer and G<i>αβγ</i> heterotrimer, as well as their signaling upon GPCR activation, is poorly understood. The present study shows that clinically used statins not only significantly disrupt PM localization of G<i>βγ</i> but also perturb GPCR-G protein signaling and associated cell behaviors. The results also demonstrate that the efficiency of prenylation inhibition by statins is G<i>γ</i> subtype-dependent and is more effective toward farnesylated G<i>γ</i> types. Since G<i>γ</i> is required for G<i>βγ</i> signaling and shows a cell- and tissue-specific subtype distribution, the present study can help understand the mechanisms underlying clinical outcomes of statin use in patients. This work also reveals the potential of statins as clinically usable drugs to control selected GPCR-G protein signaling." @default.
• W2912141728 created "2019-02-21" @default.
• W2912141728 creator A5005316378 @default.
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• W2912141728 creator A5081419905 @default.
• W2912141728 date "2019-02-14" @default.
• W2912141728 modified "2023-10-11" @default.
• W2912141728 title "Statins Perturb G<i>βγ</i>Signaling and Cell Behavior in a G<i>γ</i>Subtype Dependent Manner" @default.
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• W2912141728 doi "https://doi.org/10.1124/mol.118.114710" @default.
• W2912141728 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6402420" @default.
• W2912141728 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30765461" @default.
• W2912141728 hasPublicationYear "2019" @default.
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