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Biophys J, July 2000, p. 260-270, Vol. 79, No. 1

Block of Voltage-Dependent Calcium Channels by Aliphatic Monoamines

Aaron M. Beedle and Gerald W. Zamponi

Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta T2N 4N1, Canada

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 Ca2+ 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 Ca2+ 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-Ca2+ 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 Ba2+ 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 Ca2+ channels, with block being governed by rigid structural requirements and channel-specific state dependencies.

Biophys J, July 2000, p. 260-270, Vol. 79, No. 1
© 2000 by the Biophysical Society   0006-3495/00/07/260/11  $2.00


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