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Molecular Pharmacology

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Research ArticleArticle

Statins perturb Gβγ signaling and cell behaviors in a Gγ subtype dependent manner

Mithila Tennakoon, Dinesh Kankanamge, Kanishka Senarath, Zehra Fasih and Ajith Karunarathne
Molecular Pharmacology February 14, 2019, mol.118.114710; DOI: https://doi.org/10.1124/mol.118.114710
Mithila Tennakoon
The University of Toledo
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Dinesh Kankanamge
The University of Toledo
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Kanishka Senarath
The University of Toledo
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Zehra Fasih
The University of Toledo
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Ajith Karunarathne
The University of Toledo
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Abstract

Guanine nucleotide-binding proteins (G proteins) facilitate transduction of external signals to the cell interior, regulate a majority of 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 (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 anti-cancer drug development. Although prenylated G protein γ (Gγ) is essential for G protein coupled receptor (GPCR) mediated signaling, how mevalonate pathway inhibitors, statins, influence subcellular distribution of Gβγ dimer and Gαβγ 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 Gβγ, but also perturb GPCR-G protein signaling and associated cell behaviors. The results also demonstrate that the efficiency of prenylation-inhibition by statins is Gγ subtype-dependent and is more effective towards farnesylated Gγ types. Since Gγ is required for Gβγ signaling and it shows a cell and tissue-specific subtype distribution, the present study can help understand the mechanisms underlying clinical outcomes of statins in patients. This work also reveals the potential of statins as clinically usable drugs to control selected GPCR-G protein signaling.

  • AKT
  • Alpha-adrenergic receptors
  • Cell migration
  • Cholesterol
  • Desensitization
  • G protein-coupled receptor kinases (GPKs)
  • G protein-coupled receptors (GPCRs)
  • G proteins (GTP-binding proteins)
  • HMG-CoA reductase
  • Receptor internalization
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 103 (2)
Molecular Pharmacology
Vol. 103, Issue 2
1 Feb 2023
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Research ArticleArticle

Statins perturb Gβγ signaling and cell behaviors in a Gγ subtype dependent manner

Mithila Tennakoon, Dinesh Kankanamge, Kanishka Senarath, Zehra Fasih and Ajith Karunarathne
Molecular Pharmacology February 14, 2019, mol.118.114710; DOI: https://doi.org/10.1124/mol.118.114710

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Research ArticleArticle

Statins perturb Gβγ signaling and cell behaviors in a Gγ subtype dependent manner

Mithila Tennakoon, Dinesh Kankanamge, Kanishka Senarath, Zehra Fasih and Ajith Karunarathne
Molecular Pharmacology February 14, 2019, mol.118.114710; DOI: https://doi.org/10.1124/mol.118.114710
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