title: Block of voltage-dependent calcium channels by aliphatic monoamines.
abstract: 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.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: Beedle
authors.forename: G W
authors.initials: GW
authors.lastname: Zamponi
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000473:Alkanes / Q000494:pharmacology; D000588:Amines / Q000494:pharmacology*; D000818:Animals; D001464:Barium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D002460:Cell Line; D007851:Dodecanol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005204:Farnesol / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000085:Acetates; D000473:Alkanes; D000588:Amines; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002273:Carcinogens; D013501:Surface-Active Agents; C007548:n-dodecane; D007851:Dodecanol; D001464:Barium; D005204:Farnesol; C044215:lauryl acetate; C003935:dodecylamine