Farnesol inhibits L-type Ca2+ channels in vascular smooth muscle cells

Jean-Baptiste Roullet, Ulrich C. Luft, Hong Xue, Justin Chapman, Rostislav Bychkov, Chantal M. Roullet, Friedrich C. Luft, Hermann Haller, David A. McCarron

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Abstract

Earlier experiments with animal and human arteries have shown that farnesol, a natural 15-carbon (C15) isoprenoid, is an inhibitor of vasoconstriction (Roullet, J.B., Xue, H., Chapman, J., McDougal, P., Roullet, C. M., and McCarron, D. A. (1996) J. Clin. Invest. 97, 2364-2390). We report here that farnesol reduced KCl- and norepinephrine-dependent cytosolic Ca2+ transients in fura-2-loaded intact arteries. An effect on Ca2+ signaling was also observed in cultured aortic smooth muscle cells (A10 cells). In these cells, farnesol reduced KCl-induced [Ca2+](i) transients and mimicked the inhibitory effect of Ca2+-free medium on the [Ca2+](i) response to both 12,13-phorbol myristate acetate, a protein kinase C activator, and thapsigargin, a specific endoplasmic reticulum ATPase inhibitor. Perforated patch-clamp experiments further showed in two vascular smooth muscle cell lines (A10 and A7r5), a reversible, dose-dependent inhibitory effect of farnesol on L-type Ca2+ currents (IC50 = 2.2μM). Shorter (C10, geraniol) and longer (C20, geranylgeraniol) isoprenols were inactive. L- type Ca2+ channel blockade also occurred under tight (gigaohm) seal configuration using cell-attached, single-channel analysis, thus suggesting a possible action of farnesol from within the intracellular space. We finally demonstrated that farnesol did not affect Ca2+-sensitive pathways implicated in smooth muscle contraction, as tested with α-toxin permeabilized arteries. Altogether, our results indicate that farnesol is an inhibitor of vascular smooth muscle Ca2+ signaling with plasma membrane Ca2+ channel blocker properties. The data have implications for the endogenous and pharmacological regulation of vascular tone by farnesol or farnesol analogues.

Original languageEnglish (US)
Pages (from-to)32240-32246
Number of pages7
JournalJournal of Biological Chemistry
Volume272
Issue number51
DOIs
Publication statusPublished - Dec 19 1997

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ASJC Scopus subject areas

  • Biochemistry

Cite this

Roullet, J-B., Luft, U. C., Xue, H., Chapman, J., Bychkov, R., Roullet, C. M., ... McCarron, D. A. (1997). Farnesol inhibits L-type Ca2+ channels in vascular smooth muscle cells. Journal of Biological Chemistry, 272(51), 32240-32246. https://doi.org/10.1074/jbc.272.51.32240