Phosphorylation of Farnesol in Rat Liver Microsomes: Properties of Farnesol Kinase and Farnesyl Phosphate Kinase

Bentinger, Magnus; Grünler, Jacob; Peterson, Elisabeth; Świeżewska, Ewa; Dallner, Gustav

doi:10.1006/abbi.1998.0611

Cited by 59 publications

(50 citation statements)

References 40 publications

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“…Thus, over the time course of a typical neuronal action potential, L-type channels were the most effectively inhibited channel isoform, followed by N-type channels (IC 50 values obtained from dose-response curves for peak current inhibition (32,33). In hepatic tissue, farnesol is catabolized into farnesoic acid and dicarboxylic acids (34) or is re-phosphorylated into farnesyl pyrophosphate by a specific kinase (35,36). Multistep branches of the pathway are marked with dotted arrows for simplicity.…”

Section: Farnesol Mediates a Low Affinity Block Of All Types Of Highmentioning

confidence: 99%

Modulation of Neuronal Voltage-gated Calcium Channels by Farnesol

Roullet¹,

Spaetgens²,

Burlingame³

et al. 1999

Journal of Biological Chemistry

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The modulation of presynaptic voltage-dependent calcium channels by classical second messenger molecules such as protein kinase C and G protein ␤␥ subunits is well established and considered a key factor for the regulation of neurotransmitter release. However, little is known of other endogenous mechanisms that control the activity of these channels. Here, we demonstrate a unique modulation of N-type calcium channels by farnesol, a dephosphorylated intermediate of the mammalian mevalonate pathway. At micromolar concentrations, farnesol acts as a relatively non-discriminatory rapid open channel blocker of all types of high voltage-activated calcium channels, with a mild specificity for Ltype channels. However, at 250 nM, farnesol induces an N-type channel-specific hyperpolarizing shift in channel availability that results in ϳ50% inhibition at a typical neuronal resting potential. Additional experiments demonstrated the presence of farnesol in the brain (rodents and humans) at physiologically relevant concentrations (100 -800 pmol/g (wet weight)). Altogether, our results indicate that farnesol is a selective, high affinity inhibitor of N-type Ca 2؉ channels and raise the possibility that endogenous farnesol and the mevalonate pathway are implicated in neurotransmitter release through regulation of presynaptic voltage-gated Ca 2؉ channels.Calcium entry into the cytosol is a crucial mediator of a range of cellular responses, including cell proliferation and neurotransmitter release (1, 2). Internal calcium levels are precisely regulated through differential expression and modulation of multiple types of voltage-dependent calcium channels (3-6). These channels are key pharmacological targets, and the identification of novel means of regulating calcium channel activity remains of critical importance for the treatment of a variety of neurological disorders, including migraines, pain, and ischemia (7, 8).Molecular cloning has identified genes encoding at least nine different neuronal calcium channel ␣ 1 subunits (termed ␣ 1A through ␣ 1I ). Functional expression studies have shown that ␣ 1A encodes P-and Q-type calcium channels (9, 10); ␣ 1B defines an -conotoxin GVIA-sensitive N-type channel (11, 12); ␣ 1C , ␣ 1D , and ␣ 1F are L-type calcium channels (13-16); ␣ 1G ␣ 1H , and ␣ 1I are members of the family of T-type calcium channels (17-19); and ␣ 1E is a unique calcium channel with properties common to both high and low threshold calcium channels (20,21). The activities of voltage-dependent calcium channels are extensively modulated by cytoplasmic messenger molecules. Although the short-term modulation of these channels by protein kinases (22,23,24) and G protein ␤␥ subunits (25-31) has been well documented, little is known about mechanisms that mediate their long-term regulation.Farnesol is an isoprenoid intermediate of the mevalonate pathway, produced by dephosphorylation of farnesyl pyrophosphate ( Fig. 1) (32, 33). This pathway plays a central role in cell growth and differentiation; controls the production of ub...

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Section: Farnesol Mediates a Low Affinity Block Of All Types Of Highmentioning

confidence: 99%

Modulation of Neuronal Voltage-gated Calcium Channels by Farnesol

Roullet¹,

Spaetgens²,

Burlingame³

et al. 1999

Journal of Biological Chemistry

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“…Recently however, it has been demonstrated that both farnesol and geranylgeraniol also can be used as precursors for protein prenylation in tissue culture cells (23,24). Evidently, these prenyl alcohols can be phosphorylated in vivo by kinases and the existence of such enzymes has been established in both bacteria (25) and rat liver (26,27).…”

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confidence: 99%

Protein prenylation in spinach chloroplasts

Parmryd

Andersson

Dallner

1999

Proc. Natl. Acad. Sci. U.S.A.

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Protein prenylation in plants was studied by in vivo metabolic 3 H-mevalonate labeling in combination with a range of protein synthesis inhibitors. In spinach cotyledons, this posttranslational protein modification was found to be divided into two categories, one representing the conventional prenylation involving farnesyl and geranylgeranyl groups bound to cysteine residues via thioether linkages. This category revealed a similar pattern of prenylated proteins to that observed in mammalian cells and depends on nuclear gene expression. The other category was shown to represent a type of prenylation confined to chloroplasts. It depends on plastid gene expression and does not involve a thioether bond. The modifying isoprenoid could be released from the chloroplastic polypeptides by alkaline treatment and was identified as phytol upon GC-MS analysis. The phytol could readily be derived from all-trans-[ 3 H]farnesol, which, like all-trans-[ 3 H]geranylgeraniol, was taken up by the cotyledons, resulting in incorporation of radiolabel into proteins.

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“…Asterisks indicate significant differences from the Col-0 control (*P < 0.05, **P < 0.01 and ***P < 0.001) as determined by Student's t test. (Inoue et al, 1994;Crick et al, 1995Crick et al, , 1997Fliesler and Keller, 1995;Westfall et al, 1997;Bentinger et al, 1998;Thai et al, 1999). Here, we show that Arabidopsis membranes possess farnesol kinase activity and that ATP, CTP, GTP and UTP are phosphoryl donor substrates of farnesol kinase (Figure 1).…”

Section: Aba Regulation Of Folk Gene Expressionmentioning

confidence: 54%

“…However, the physiological role of farnesyl diphosphatase is not clear. Indeed, farnesol is toxic to plant cells at high concentrations, and numerous studies have demonstrated the phosphorylation of farnesol to farnesyl phosphate (FP) and subsequent phosphorylation of FP to FPP (Inoue et al, 1994;Crick et al, 1995Crick et al, , 1997Fliesler and Keller, 1995;Westfall et al, 1997;Bentinger et al, 1998;Thai et al, 1999;Hemmerlin and Bach, 2000;Hemmerlin et al, 2006). For example, when tobacco microsomal membranes were used as a source of kinase activity, phosphorylation of farnesol to FP occurred in the presence of CTP, GTP or UTP as a phosphoryl donor, but phosphorylation of FP to FPP occurred only in the presence of CTP as a phosphoryl donor (Thai et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Farnesol kinase is involved in farnesol metabolism, ABA signaling and flower development in Arabidopsis

2011

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SUMMARYFarnesol, which is toxic to plant cells at high concentrations, is sequentially phosphorylated to farnesyl phosphate and farnesyl diphosphate. However, the genes responsible for the sequential phosphorylation of farnesol have not been identified and the physiological role of farnesol phosphorylation has not been fully elucidated. To address these questions, we confirmed the presence of farnesol kinase activity in Arabidopsis (Arabidopsis thaliana) membranes and identified the corresponding gene (At5g58560, FOLK). Heterologous expression in recombinant yeast cells established farnesol as the preferred substrate of the FOLK-encoded kinase. Moreover, loss-of-function mutations in the FOLK gene abolished farnesol kinase activity, caused an abscisic acid-hypersensitive phenotype and promoted the development of supernumerary carpels under water-stress conditions. In wild-type plants, exogenous abscisic acid repressed FOLK gene expression. These observations demonstrate a role for farnesol kinase in negative regulation of abscisic acid signaling, and provide molecular evidence for a link between farnesol metabolism, abiotic stress signaling and flower development.

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Phosphorylation of Farnesol in Rat Liver Microsomes: Properties of Farnesol Kinase and Farnesyl Phosphate Kinase

Cited by 59 publications

References 40 publications

Modulation of Neuronal Voltage-gated Calcium Channels by Farnesol

Modulation of Neuronal Voltage-gated Calcium Channels by Farnesol

Protein prenylation in spinach chloroplasts

Farnesol kinase is involved in farnesol metabolism, ABA signaling and flower development in Arabidopsis

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