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. 2000 Jul;79(1):260–270. doi: 10.1016/S0006-3495(00)76288-6

Block of voltage-dependent calcium channels by aliphatic monoamines.

A M Beedle 1, G W Zamponi 1
PMCID: PMC1300930  PMID: 10866952

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.

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Selected References

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  1. Aungst B. J., Blake J. A., Hussain M. A. Contributions of drug solubilization, partitioning, barrier disruption, and solvent permeation to the enhancement of skin permeation of various compounds with fatty acids and amines. Pharm Res. 1990 Jul;7(7):712–718. doi: 10.1023/a:1015859320604. [DOI] [PubMed] [Google Scholar]
  2. Bangalore R., Baindur N., Rutledge A., Triggle D. J., Kass R. S. L-type calcium channels: asymmetrical intramembrane binding domain revealed by variable length, permanently charged 1,4-dihydropyridines. Mol Pharmacol. 1994 Oct;46(4):660–666. [PubMed] [Google Scholar]
  3. Bech-Hansen N. T., Naylor M. J., Maybaum T. A., Pearce W. G., Koop B., Fishman G. A., Mets M., Musarella M. A., Boycott K. M. Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness. Nat Genet. 1998 Jul;19(3):264–267. doi: 10.1038/947. [DOI] [PubMed] [Google Scholar]
  4. Beeler T., Gable K., Dunn T. Activation of divalent cation influx into S. cerevisiae cells by hypotonic downshift. J Membr Biol. 1997 Nov 1;160(1):77–83. doi: 10.1007/s002329900296. [DOI] [PubMed] [Google Scholar]
  5. Bielefeld D. R., Hadley R. W., Vassilev P. M., Hume J. R. Membrane electrical properties of vesicular Na-Ca exchange inhibitors in single atrial myocytes. Circ Res. 1986 Oct;59(4):381–389. doi: 10.1161/01.res.59.4.381. [DOI] [PubMed] [Google Scholar]
  6. Boland L. M., Morrill J. A., Bean B. P. omega-Conotoxin block of N-type calcium channels in frog and rat sympathetic neurons. J Neurosci. 1994 Aug;14(8):5011–5027. doi: 10.1523/JNEUROSCI.14-08-05011.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bourinet E., Soong T. W., Sutton K., Slaymaker S., Mathews E., Monteil A., Zamponi G. W., Nargeot J., Snutch T. P. Splicing of alpha 1A subunit gene generates phenotypic variants of P- and Q-type calcium channels. Nat Neurosci. 1999 May;2(5):407–415. doi: 10.1038/8070. [DOI] [PubMed] [Google Scholar]
  8. Catterall W. A. Functional subunit structure of voltage-gated calcium channels. Science. 1991 Sep 27;253(5027):1499–1500. doi: 10.1126/science.1654596. [DOI] [PubMed] [Google Scholar]
  9. Cribbs L. L., Lee J. H., Yang J., Satin J., Zhang Y., Daud A., Barclay J., Williamson M. P., Fox M., Rees M. Cloning and characterization of alpha1H from human heart, a member of the T-type Ca2+ channel gene family. Circ Res. 1998 Jul 13;83(1):103–109. doi: 10.1161/01.res.83.1.103. [DOI] [PubMed] [Google Scholar]
  10. Dickson C. T., Mena A. R., Alonso A. Electroresponsiveness of medial entorhinal cortex layer III neurons in vitro. Neuroscience. 1997 Dec;81(4):937–950. doi: 10.1016/s0306-4522(97)00263-7. [DOI] [PubMed] [Google Scholar]
  11. Ellis S. B., Williams M. E., Ways N. R., Brenner R., Sharp A. H., Leung A. T., Campbell K. P., McKenna E., Koch W. J., Hui A. Sequence and expression of mRNAs encoding the alpha 1 and alpha 2 subunits of a DHP-sensitive calcium channel. Science. 1988 Sep 23;241(4873):1661–1664. doi: 10.1126/science.2458626. [DOI] [PubMed] [Google Scholar]
  12. Fletcher C. F., Lutz C. M., O'Sullivan T. N., Shaughnessy J. D., Jr, Hawkes R., Frankel W. N., Copeland N. G., Jenkins N. A. Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell. 1996 Nov 15;87(4):607–617. doi: 10.1016/s0092-8674(00)81381-1. [DOI] [PubMed] [Google Scholar]
  13. Fox J. A. Irreversible and reversible blockade of IMR32 calcium channel currents by synthetic MVIIA and iodinated MVIIC omega-conopeptides. Pflugers Arch. 1995 Apr;429(6):873–875. doi: 10.1007/BF00374813. [DOI] [PubMed] [Google Scholar]
  14. Hawthorn M. H., Ferrante J. N., Kwon Y. W., Rutledge A., Luchowski E., Bangalore R., Triggle D. J. Effect of an homologous series of aliphatic alcohols on neuronal and smooth muscle voltage-dependent Ca2+ channels. Eur J Pharmacol. 1992 Dec 15;229(2-3):143–148. doi: 10.1016/0014-2999(92)90548-i. [DOI] [PubMed] [Google Scholar]
  15. Higuchi H., Nakano K., Kim C. H., Li B. S., Kuo C. H., Taira E., Miki N. Ca2+/calmodulin-dependent transcriptional activation of neuropeptide Y gene induced by membrane depolarization: determination of Ca(2+)- and cyclic AMP/phorbol 12-myristate 13-acetate-responsive elements. J Neurochem. 1996 May;66(5):1802–1809. doi: 10.1046/j.1471-4159.1996.66051802.x. [DOI] [PubMed] [Google Scholar]
  16. Leaf A. Omega-3 fatty acids and prevention of ventricular fibrillation. Prostaglandins Leukot Essent Fatty Acids. 1995 Feb-Mar;52(2-3):197–198. doi: 10.1016/0952-3278(95)90022-5. [DOI] [PubMed] [Google Scholar]
  17. Lee J. H., Daud A. N., Cribbs L. L., Lacerda A. E., Pereverzev A., Klöckner U., Schneider T., Perez-Reyes E. Cloning and expression of a novel member of the low voltage-activated T-type calcium channel family. J Neurosci. 1999 Mar 15;19(6):1912–1921. doi: 10.1523/JNEUROSCI.19-06-01912.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lemos J. R., Nowycky M. C. Two types of calcium channels coexist in peptide-releasing vertebrate nerve terminals. Neuron. 1989 May;2(5):1419–1426. doi: 10.1016/0896-6273(89)90187-6. [DOI] [PubMed] [Google Scholar]
  19. McCleskey E. W. Calcium channels: cellular roles and molecular mechanisms. Curr Opin Neurobiol. 1994 Jun;4(3):304–312. doi: 10.1016/0959-4388(94)90090-6. [DOI] [PubMed] [Google Scholar]
  20. Mintz I. M., Venema V. J., Swiderek K. M., Lee T. D., Bean B. P., Adams M. E. P-type calcium channels blocked by the spider toxin omega-Aga-IVA. Nature. 1992 Feb 27;355(6363):827–829. doi: 10.1038/355827a0. [DOI] [PubMed] [Google Scholar]
  21. Ophoff R. A., Terwindt G. M., Vergouwe M. N., van Eijk R., Oefner P. J., Hoffman S. M., Lamerdin J. E., Mohrenweiser H. W., Bulman D. E., Ferrari M. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996 Nov 1;87(3):543–552. doi: 10.1016/s0092-8674(00)81373-2. [DOI] [PubMed] [Google Scholar]
  22. Pearson W. L., Nichols C. G. Block of the Kir2.1 channel pore by alkylamine analogues of endogenous polyamines. J Gen Physiol. 1998 Sep;112(3):351–363. doi: 10.1085/jgp.112.3.351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Perez-Reyes E., Cribbs L. L., Daud A., Lacerda A. E., Barclay J., Williamson M. P., Fox M., Rees M., Lee J. H. Molecular characterization of a neuronal low-voltage-activated T-type calcium channel. Nature. 1998 Feb 26;391(6670):896–900. doi: 10.1038/36110. [DOI] [PubMed] [Google Scholar]
  24. Philipson K. D. Interaction of charged amphiphiles with Na+-Ca2+ exchange in cardiac sarcolemmal vesicles. J Biol Chem. 1984 Nov 25;259(22):13999–14002. [PubMed] [Google Scholar]
  25. Roullet J. B., Spaetgens R. L., Burlingame T., Feng Z. P., Zamponi G. W. Modulation of neuronal voltage-gated calcium channels by farnesol. J Biol Chem. 1999 Sep 3;274(36):25439–25446. doi: 10.1074/jbc.274.36.25439. [DOI] [PubMed] [Google Scholar]
  26. Terrar D. A., White E. Mechanisms and significance of calcium entry at positive membrane potentials in guinea-pig ventricular muscle cells. Q J Exp Physiol. 1989 Mar;74(2):121–139. doi: 10.1113/expphysiol.1989.sp003250. [DOI] [PubMed] [Google Scholar]
  27. The Sicilian gambit. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. Circulation. 1991 Oct;84(4):1831–1851. doi: 10.1161/01.cir.84.4.1831. [DOI] [PubMed] [Google Scholar]
  28. Tomlinson W. J., Stea A., Bourinet E., Charnet P., Nargeot J., Snutch T. P. Functional properties of a neuronal class C L-type calcium channel. Neuropharmacology. 1993 Nov;32(11):1117–1126. doi: 10.1016/0028-3908(93)90006-o. [DOI] [PubMed] [Google Scholar]
  29. Tsien R. W., Ellinor P. T., Horne W. A. Molecular diversity of voltage-dependent Ca2+ channels. Trends Pharmacol Sci. 1991 Sep;12(9):349–354. doi: 10.1016/0165-6147(91)90595-j. [DOI] [PubMed] [Google Scholar]
  30. Wang G. K., Simon R., Wang S. Y. Quaternary ammonium compounds as structural probes of single batrachotoxin-activated Na+ channels. J Gen Physiol. 1991 Nov;98(5):1005–1024. doi: 10.1085/jgp.98.5.1005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Williams M. E., Brust P. F., Feldman D. H., Patthi S., Simerson S., Maroufi A., McCue A. F., Veliçelebi G., Ellis S. B., Harpold M. M. Structure and functional expression of an omega-conotoxin-sensitive human N-type calcium channel. Science. 1992 Jul 17;257(5068):389–395. doi: 10.1126/science.1321501. [DOI] [PubMed] [Google Scholar]
  32. Williams M. E., Feldman D. H., McCue A. F., Brenner R., Velicelebi G., Ellis S. B., Harpold M. M. Structure and functional expression of alpha 1, alpha 2, and beta subunits of a novel human neuronal calcium channel subtype. Neuron. 1992 Jan;8(1):71–84. doi: 10.1016/0896-6273(92)90109-q. [DOI] [PubMed] [Google Scholar]
  33. Williams M. E., Marubio L. M., Deal C. R., Hans M., Brust P. F., Philipson L. H., Miller R. J., Johnson E. C., Harpold M. M., Ellis S. B. Structure and functional characterization of neuronal alpha 1E calcium channel subtypes. J Biol Chem. 1994 Sep 2;269(35):22347–22357. [PubMed] [Google Scholar]
  34. Zamponi G. W., Doyle D. D., French R. J. Fast lidocaine block of cardiac and skeletal muscle sodium channels: one site with two routes of access. Biophys J. 1993 Jul;65(1):80–90. doi: 10.1016/S0006-3495(93)81042-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Zamponi G. W., Doyle D. D., French R. J. State-dependent block underlies the tissue specificity of lidocaine action on batrachotoxin-activated cardiac sodium channels. Biophys J. 1993 Jul;65(1):91–100. doi: 10.1016/S0006-3495(93)81043-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Zhang J. F., Randall A. D., Ellinor P. T., Horne W. A., Sather W. A., Tanabe T., Schwarz T. L., Tsien R. W. Distinctive pharmacology and kinetics of cloned neuronal Ca2+ channels and their possible counterparts in mammalian CNS neurons. Neuropharmacology. 1993 Nov;32(11):1075–1088. doi: 10.1016/0028-3908(93)90003-l. [DOI] [PubMed] [Google Scholar]

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