Modulation of neuronal voltage-gated calcium channels by farnesol

The modulation of presynaptic voltage-dependent calcium channels by classic al second messenger molecules such as protein kinase C and G protein beta g amma subunits is well established and considered a key factor for the regul ation of neurotransmitter release. However, little is known of other endoge nous mechanisms that control the activity of these channels. Here, we demon strate a unique modulation of N-type calcium channels by farnesol, a dephos phorylated 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, w ith a mild specificity for L-type channels. However, at 250 nM, farnesol in duces an N-type channel-specific hyperpolarizing shift in channel availabil ity that results in similar to 50% 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 farnes ol is a selective, high affinity inhibitor of N-type Ca2+ channels and rais e the possibility that endogenous farnesol and the mevalonate pathway are i mplicated in neurotransmitter release through regulation of presynaptic vol tage-gated Ca2+ channels.