Farnesyl analogues inhibit vasoconstriction in animal and human arteries.

Roullet, Jean Baptiste; Xue, Hong; Chapman, Justin; McDougal, Patrick G.; Roullet, Chantal; McCarron, David A.

doi:10.1172/jci118682

Cited by 34 publications

(19 citation statements)

References 43 publications

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“…1) (40, 41). Other studies have suggested a role for farnesol in tumor cell proliferation and apoptosis (42)(43)(44) and as an endogenous regulator of vascular tone and blood pressure (37,45,46). Our data raise the possibility that farnesol may contribute to the intimate regulation of brain function via regulation of N-type calcium channel activity.…”

Section: Figsupporting

confidence: 58%

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: Figsupporting

confidence: 58%

Modulation of Neuronal Voltage-gated Calcium Channels by Farnesol

Roullet¹,

Spaetgens²,

Burlingame³

et al. 1999

Journal of Biological Chemistry

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“…Although farnesol inhibits phosphatidylcholine synthesis in human leukemia cells, leading to apoptosis (32,33), and inhibits vasoconstriction in arteries (34), no effects of farnesol or its metabolites on skin have been described before our studies. Despite both the identification of FXR in several extracutaneous tissues and the identification of certain of its activators, the actual ligands, as well as the function of this signaling pathway, remain unknown.…”

Section: Discussionmentioning

confidence: 77%

Activators of the nuclear hormone receptors PPARalpha and FXR accelerate the development of the fetal epidermal permeability barrier.

Hanley¹,

Jiang²,

Crumrine³

et al. 1997

J. Clin. Invest.

155

124

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“…sive urinary excretion of farnesol-derived dicarboxylic acids (41), indicating the elevation of the plasma concentration of farnesol and its metabolites. Farnesol has recently been found to be a biologically active substance; it inhibits arterial vasoconstriction through blocking L-type Ca 2ϩ channels in vascular smooth muscle cells (42,43). Other studies have reported the existence of a farnesol-specific, orphan nuclear receptor in vertebrate cells, the farnesoid X-activated receptor, but its precise functions remain unknown (44).…”

Section: Discussionmentioning

confidence: 99%

Embryonic Lethality and Defective Neural Tube Closure in Mice Lacking Squalene Synthase

Tozawa¹,

Ishibashi²,

Osuga³

et al. 1999

Journal of Biological Chemistry

123

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Squalene synthase (SS) catalyzes the reductive headto-head condensation of two molecules of farnesyl diphosphate to form squalene, the first specific intermediate in the cholesterol biosynthetic pathway. We used gene targeting to knock out the mouse SS gene. The mice heterozygous for the mutation (SS؉/؊) were apparently normal. SS؉/؊ mice showed 60% reduction in the hepatic mRNA levels of SS compared with SS؉/؉ mice. Consistently, the SS enzymatic activities were reduced by 50% in the liver and testis. Nevertheless, the hepatic cholesterol synthesis was not different between SS؉/؊ and SS؉/؉ mice, and plasma lipoprotein profiles were not different irrespective of the presence of the low density lipoprotein receptor, indicating that SS is not a rate-limiting enzyme in the cholesterol biosynthetic pathway. The mice homozygous for the disrupted SS gene (SS؊/؊) were embryonic lethal around midgestation. E9.5-10.5 SS؊/؊ embryos exhibited severe growth retardation and defective neural tube closure. The lethal phenotype was not rescued by supplementing the dams either with dietary squalene or cholesterol. We speculate that cholesterol is required for the development, particularly of the nervous system, and that the chorioallantoic circulatory system is not mature enough to supply the rapidly growing embryos with maternal cholesterol at this developmental stage.

show abstract

Farnesyl analogues inhibit vasoconstriction in animal and human arteries.

Cited by 34 publications

References 43 publications

Modulation of Neuronal Voltage-gated Calcium Channels by Farnesol

Modulation of Neuronal Voltage-gated Calcium Channels by Farnesol

Activators of the nuclear hormone receptors PPARalpha and FXR accelerate the development of the fetal epidermal permeability barrier.

Embryonic Lethality and Defective Neural Tube Closure in Mice Lacking Squalene Synthase

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