TY - JOUR
T1 - Modulation of neuronal voltage-gated calcium channels by farnesol
AU - Roullet, Jean Baptiste
AU - Spaetgens, Renee L.
AU - Burlingame, Terry
AU - Feng, Zhong Ping
AU - Zamponi, Gerald W.
PY - 1999/9/3
Y1 - 1999/9/3
N2 - The modulation of presynaptic voltage-dependent calcium channels by classical second messenger molecules such as protein kinase C and G protein βγ subunits is well established and considered a key factor for the regulation of neurotransmitter release. However, little is known of other endogenous mechanisms that control the activity of these channels. Here, we demonstrate a unique modulation of N-type calcium channels by farnesol, a dephosphorylated 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, with a mild specificity for L-type channels. However, at 250 nM, farnesol induces an N-type channel-specific hyperpolarizing shift in channel availability that results in ~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 farnesol is a selective, high affinity inhibitor of N-type Ca2+ channels and raise the possibility that endogenous farnesol and the mevalonate pathway are implicated in neurotransmitter release through regulation of presynaptic voltage-gated Ca2+ channels.
AB - The modulation of presynaptic voltage-dependent calcium channels by classical second messenger molecules such as protein kinase C and G protein βγ subunits is well established and considered a key factor for the regulation of neurotransmitter release. However, little is known of other endogenous mechanisms that control the activity of these channels. Here, we demonstrate a unique modulation of N-type calcium channels by farnesol, a dephosphorylated 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, with a mild specificity for L-type channels. However, at 250 nM, farnesol induces an N-type channel-specific hyperpolarizing shift in channel availability that results in ~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 farnesol is a selective, high affinity inhibitor of N-type Ca2+ channels and raise the possibility that endogenous farnesol and the mevalonate pathway are implicated in neurotransmitter release through regulation of presynaptic voltage-gated Ca2+ channels.
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U2 - 10.1074/jbc.274.36.25439
DO - 10.1074/jbc.274.36.25439
M3 - Article
C2 - 10464274
AN - SCOPUS:0033520286
SN - 0021-9258
VL - 274
SP - 25439
EP - 25446
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 36
ER -