Statins Perturb GβγSignaling and Cell Behavior in a GγSubtype Dependent Manner

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 g (Gg) is essential for G protein-coupled receptor (GPCR)-mediated signaling, how mevalonate pathway inhibitors, statins, influence subcellular distribution of Gbg dimer and Gabg 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 Gbg but also perturb GPCR-G protein signaling and associated cell behaviors. The results also demonstrate that the efficiency of prenylation inhibition by statins is Gg subtype-dependent and is more effective toward farnesylated Gg types. Since Gg is required for Gbg 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.

Synthesis of the 6-Substituted Imidazo[1,2-a]Pyridine-3-yl-2- Phosphonopropionic Acids as Potential Inhibitors of Rab Geranylgeranyl Transferase

“…Even though it is the inhibitor of more upstream enzyme of mevalonate pathway, HMG-CoA reductase, and it is expected that treatment of cells with lovastatin should prevent the Ras accumulation at the membrane, we observed the failure of lovastatin to cause mislocalization of Ras. However, our observations of the lack of Ras inhibition by lovastatin in HeLa cells is in accordance with the results of Tennakoon et al (2019). They compared how different statins (fluvastatin, atorvastatin, lovastatin) attenuate prenylation of Ras superfamily members in HeLa cells, showing that HeLa cells exposed to lovastatin exhibited negligible inhibition of both Ras members.…”

Dissociation of the G protein βγ from the Gq–PLCβ complex partially attenuates PIP2 hydrolysis

“…3 B ). PM-targeted Venus–GRK3ct has previously been used to sequester free Gβγ, preventing Gβγ–effector interactions ( 48 , 49 ). A significant difference between the extent of PIP2 hydrolysis in cells expressing PM–GRK3ct compared with cells expressing cytosolic GRK3ct was observed ( Fig.…”

Myeloid HMG-CoA Reductase Determines Adipose Tissue Inflammation, Insulin Resistance, and Hepatic Steatosis in Diet-Induced Obese Mice

“…More specifically, G-protein subtypes g2 and 3, which are essential for intracellular signaling of CCR2 in macrophages, are geranylgeranylated (21). Fluvastatin inhibits the migration of RAW264.7 cells by decreasing PI(3) K-mediated production of phosphatidylinositol (3,4,5)trisphosphate (22), suggesting that similar defective downstream signaling underlies the impaired chemotaxis of Hmgcr m2/m2 TGEMs. It is also possible that decreased supply of GGPP impairs geranylgeranylation of Rab GTPases, which are catalyzed by GGTase 2, also known as Rab GGTase, thereby impairing cell migration (23).…”