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

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

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
StatePublished - Dec 19 1997

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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