Modulation of neuronal voltage-gated calcium channels by farnesol.
The modulation of presynaptic voltage-dependent calcium channels by classical second messenger molecules such as protein kinase C and G protein betagamma 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 approximately 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 Ca(2+) channels and raise the possibility that endogenous farnesol and the mevalonate pathway are implicated in neurotransmitter release through regulation of presynaptic voltage-gated Ca(2+) channels.
Roullet
J B
JB
Division of Nephrology, Hypertension, and Clinical Pharmacology, Oregon Health Sciences University, Portland, Oregon 97201, USA.
Spaetgens
R L
RL
Burlingame
T
T
Feng
Z P
ZP
Zamponi
G W
GW
D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology*; D002460:Cell Line; D005204:Farnesol / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D014162:Transfection
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D005204:Farnesol