Farnesol blocks the L-type Ca2+ channel by targeting the alpha(1C) subunit

We recently demonstrated that farnesol, a 15-carbon isoprenoid, blocks L-ty pe Ca2+ channels in vascular smooth muscle cells. To elucidate farnesol's m echanism of action, we performed whole-cell and perforated-patch clamp expe riments in rat aortic A7r5 cells and in Chinese hamster ovary (CHO) C9 cell s expressing smooth muscle Ca2+ channel a,, subunits. Farnesol dose-depende ntly and voltage-independently inhibited Ba2+ currents in both A7r5 and CHO C9 cells, with similar half-maximal inhibitions at 2.6 and 4.3 mmol/L, resp ectively (P=NS). In both cell lines, current inhibition by farnesol was pro minent over the whole voltage range without changes in the current-voltage relationship peaks. Neither intracellular infusion of the stable GDP analog ue guanosine-5' -O-(2-thiodiphosphate) (100 mmol/L) via the patch pipette n or strong conditioning membrane depolarization prevented the inhibitory eff ect of farnesol, which indicates G protein-independent inhibition of Ca2+ c hannels. In an analysis of the steady-state inactivation curve for voltage dependence, farnesol induced a significant, negative shift (approximate to 10 mV) of the potential causing 50% channel inactivation in both cell lines (P<0.001). In contrast, the steepness factor characterizing the voltage se nsitivity of the channels was unaffected. Unlike pharmacological Ca2+ chann el blockers, farnesol blocked Ca2+ currents in the resting state: initial b lock was 63+/-8% in A7r5 cells and 50+/-9% in CHOC9 cells at a holding pote ntial of -80 mV. We then gave 500 mg/kg body weight farnesol by gavage to S abra hypertensive and normotensive rats and found that farnesol reduced blo od pressure significantly in the hypertensive strain for at least 48 hours. We conclude that farnesol may represent an endogenous smooth muscle L-type Ca2+ channel antagonist. Because farnesol is active in cells expressing on ly the pore-forming a, subunit, the data further suggest that this subunit represents the molecular target for farnesol binding and principal action. Finally, farnesol has a blood pressure-lowering action that may be relevant in vivo.