MOdulation of Voltage-Gated Calcium Channels by Farnesol

The modulation of presynaptic voltage-dependent calcium channels is a key factor for the regulation of neurotransmitter release. Regulation of these channels by classical second messenger molecules such as protein kinase C and G protein By subunits has been described extensively, yet little is known of additional endogenous mechanisms which control presynaptic calcium channel activity. Hère, we show a unique modulation of N-type calcium channels by farnesol, a dephosphorylated precursor to the mammalian mevalonate pathway. When applied exogenously to calcium channels expressed in HEK cells, 25 |iM farnesol produces a rapid, but relatively nondiscriminatory pore block of all types of high-voltage activated calcium channels with some preference for L-type channels. However, at nM concentrations, farnesol induces an N-type channel selective negative shift in channel availability which causes a 50% inhibition at a typical neuronal resting potential of -70 mV. Using mass spectroscopy, we have determined the free farnesol concentration in human brain tissue to range from 100 to 200 nM, indicating that N-type channel modulation occurs at physiologically relevant farnesol levels. Our results indicate that farnesol is an endogenous modulator of N-type calcium channels, and suggest a novel mechanism for regulating N-type channel activity, and thus, neurotransmission.