Block of Voltage-Dependent Calcium Channels by Aliphatic Monoamines

We have recently identified farnesol, an intermediate in the mevalonate pathway, as a potent endogenous modulator and blocker of N-type calcium channels (Roullet, J. B., R. L. Spaetgens, T. Burlingame, and G. W. Zamponi. 1999. J. Biol. Chem. 274:25439–25446). Here, we investigate the action of struc...

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Bibliographic Details
Published in:Biophysical journal 2000-07, Vol.79 (1), p.260-270
Main Authors: Beedle, Aaron M., Zamponi, Gerald W.
Format: Article
Language:English
Subjects:
Acetates - pharmacology
Alkanes - pharmacology
Amines - pharmacology
Animals
Barium - pharmacology
Calcium
Calcium Channel Blockers - pharmacology
Calcium Channels - drug effects
Calcium Channels - metabolism
Carcinogens - pharmacology
Cell Line
Cellular biology
Dodecanol - pharmacology
Dose-Response Relationship, Drug
Farnesol - analogs & derivatives
Farnesol - pharmacology
Humans
Kidney - cytology
Kidney - drug effects
Kidney - metabolism
Kidneys
Patch-Clamp Techniques
Rats
Structure-Activity Relationship
Surface-Active Agents - pharmacology
Transfection
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Summary:We have recently identified farnesol, an intermediate in the mevalonate pathway, as a potent endogenous modulator and blocker of N-type calcium channels (Roullet, J. B., R. L. Spaetgens, T. Burlingame, and G. W. Zamponi. 1999. J. Biol. Chem. 274:25439–25446). Here, we investigate the action of structurally related compounds on various types of voltage-dependent Ca 2+ channels transiently expressed in human embryonic kidney cells. 1-Dodecanol, despite sharing the 12-carbon backbone and headgroup of farnesol, exhibited a significantly lower blocking affinity for N-type Ca 2+ channels. Among several additional 12-carbon compounds tested, dodecylamine (DDA) mediated the highest affinity inhibition of N-type channels, indicating that the functional headgroup is a critical determinant of blocking affinity. This inhibition was concentration-dependent and relatively non-discriminatory among N-, L-, P/Q-, and R-Ca 2+ channel subtypes. However, whereas L-type channels exhibited predominantly resting channel block, the non-L-type isoforms showed substantial rapid open channel block manifested by a speeding of the apparent time course of current decay and block of the inactivated state. Consistent with these findings, we observed significant frequency-dependence of block and dependence on external Ba 2+ concentration for N-type, but not L-type, channels. We also systematically investigated the drug structural requirements for N-type channel inhibition. Blocking affinity varied with carbon chain length and showed a clear maximum at C12 and C13, with shorter and longer molecules producing progressively weaker peak current block. Overall, our data indicate that aliphatic monoamines may constitute a novel class of potent inhibitors of voltage-dependent Ca 2+ channels, with block being governed by rigid structural requirements and channel-specific state dependencies.
ISSN:0006-3495
1542-0086
DOI:10.1016/S0006-3495(00)76288-6