Pharmacology of High-Conductance, Ca2+-Activated Potassium Channels

  • Maria L. Garcia
  • Gregory J. Kaczorowski

Abstract

Potassium channels represent a diverse family of ion channels whose members display the common property of being highly selectivity for potassium as the conducting ion. Support for the idea of the large diversity of potassium channels is gained from sequencing the Caenorhabditis elegans genome. It is predicted that about 100 K+ channel subunits exist in this organism. These K+ channel subunits belong to eight conserved K+ channel families (Wei et al., 1996), and the high-conductance, Ca2+-activated K+ (BKCa) channel is a representative member of one of these families. BKCa channels are widely distributed in both electrically excitable and nonexcitable cells (Latorre et al., 1989; McManus, 1991), are activated by both voltage and intracellular Ca2+, and display a high conductance, as well as a high selectivity for K+. They regulate excitation—contraction coupling processes in vascular, airway, bladder, and other types of smooth muscle and also control transmitter release from neuroendocrine tissue. In nonexcitable cells, BKCa channels regulate fluid secretion and cell volume. In various tissues, BKCa channels are modulated by exogenous ligands signaling through their respective membrane receptors. Regulatory mechanisms such as phosphorylation, interaction with GTP-binding proteins, or direct modulation by intracellular second messengers have been identified and charcterized.

Keywords

Fermentation Adduct Glutamine Flavonoid Thiol 

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References

  1. Adelman, J. P., Shen, K.-Z., Kavanaugh, M. P., Warren, R. A., Wu, Y.-N., Lagrutta, A., Bond, C. T., and North, R. A., 1992, Calcium-activated potassium channels expressed from cloned complementary DNAs,Neuron 9:209–216.PubMedCrossRefGoogle Scholar
  2. Anderson, C. S., MacKinnon, R., Smith, C., and Miller, C., 1988, Charybdotoxin block of single Ca2+ activated K+ channels. Effects of channel gating, voltage, and ionic strength, J. Gen. Physiol. 91:317–333.PubMedCrossRefGoogle Scholar
  3. Bontems, F., Roumestand, C., Boyot, P., Gilquin, B., Doljansky, Y., Menez, A., and Toma, F., 1991a, Three-dimensional structure of natural charybdotoxin in aqueous solution by 1H-NMR: Charybdotoxin possesses a structural motif found in other scorpion toxins, Eur. J. Biochem. 196:19–28.PubMedCrossRefGoogle Scholar
  4. Bontems, F., Roumestand, C., Gilquin, B., Menez, A., and Toma, F., 1991b, Refined structure of charybdotoxin : Common motifs in scorpion toxins and insect defensins, Science 254:1521–1523.PubMedCrossRefGoogle Scholar
  5. Bontems, F., Gilquin, B., Roumestand, C., Menez, A., and Toma, F., 1992, Analysis of side chain organization on a refined model of charybdotoxin; structural and functional implications, Biochemistry 31:7756–7764.PubMedCrossRefGoogle Scholar
  6. Butler, A., Tsunoda, S., McCobb, D. P., Wei, A., and Salkoff, L., 1993, mSlo, a complex mouse gene encoding “maxi” calcium-activated potassium channels, Science 261:221–224.PubMedCrossRefGoogle Scholar
  7. Candia, S., Garcia, M. L., and Latorre, R., 1992, Mode of action of iberiotoxin, a potent blocker of the large conductance Ca2+-activated K+ channel, Biophys. J. 63:583–590.PubMedCrossRefGoogle Scholar
  8. Chang, C.-P., Dworetzky, S. I., Wang, J., and Goldstein, M. E., 1997, Differential expression of the α and β subunits of the large-conductance calcium-activated potassium channel: Implications for channel diversity,Mol. Brain Res. 45:33–40.PubMedCrossRefGoogle Scholar
  9. Cui, J., Cox, D. H., and Aldrich, R. W., 1997, Intrinsic voltage dependence and Ca2+ regulation of mslo large conductance Ca-activated K+ channels, J. Gen. Physiol. 5:647–673.CrossRefGoogle Scholar
  10. DeFarias, F. P., Carvalho, M. F., Lee, S. H., Kaczorowski, G. J., and Suarez-Kurtz, G., 1996, Effects of the K+ channel blockers paspalitrem C and paxilline on mammalian smooth muscle, Eur. J. Pharmacol 314:123–128.PubMedCrossRefGoogle Scholar
  11. Diaz, L., Meera, P., Amigo, J., Stefani, E., Alvarez, O., Toro, L., and Latorre, R., 1998, Role of the S4 segment in a voltage-dependent calcium-sensitive potassium (hSlo) channel, J. Biol. Chem. 273:32430–32436.PubMedCrossRefGoogle Scholar
  12. Ding, J. P., Li, Z. W., and Lingle, C. J., 1998, Inactivating BK channels in rat chromaffin cells may arise from heteromultimeric assembly of distinct inactivation-competent and noninactivating subunits,Biophys. J. 74:268–289.PubMedCrossRefGoogle Scholar
  13. Dworetzky, S. I., Trojnacki, J. T., and Gribkoff, V. K., 1994, Cloning and expression of a human large-conductance calcium-activated potassium channel, Mol. Brain Res. 27:189–193.PubMedCrossRefGoogle Scholar
  14. Dworetzky, S. I., Boissard, C. G., Lum-Ragan, J. T., McKay, M. C., Post-Munson, D. J., Trojnacki, J. T., Chang, C.-P., and Gribkoff, V. K., 1996, Phenotypic alteration of a human BK (hSlo) channel by hSloβ subunit coexpression: Changes in blocker sensitivity, activation/relaxation and inactivation kinetics, and protein kinase A modulation, J. Neurosci. 16 4543–4550.PubMedGoogle Scholar
  15. Garcia, M. L., Hanner, M., Knaus, H.-G., Koch, R., Schmalhofer, W., Slaughter, R. S., and Kaczorowski, G. J., 1997, Pharmacology of potassium channels, Adv. Pharmacol. 39:425–471.PubMedCrossRefGoogle Scholar
  16. Garcia-Calvo, M., Knaus, H.-G., McManus, O. B., Giangiacomo, K. M., Kaczorowski, G. J., and Garcia, M. L., 1994, Purification and reconstitution of the high-conductance calcium-activated potassium channel from tracheal smooth muscle, J. Biol. Chem. 269:676–682.PubMedGoogle Scholar
  17. Giangiacomo, K. M., Garcia, M. L., and McManus, O. B., 1992, Mechanism of iberiotoxin block of the large-conductance calcium-activated potassium channel from bovine aortic smooth muscle, Biochemistry 31:6719–6727.PubMedCrossRefGoogle Scholar
  18. Giangiacomo, K. M., Garcia-Calvo, M., Knaus, H.-G., Mullmann, T. J., Garcia, M. L., and McManus, O., 1995, Functional reconstitution of the large-conductance, calcium-activated potassium channel purified from bovine aortic smooth muscle,Biochemistry 34:15849–15862.PubMedCrossRefGoogle Scholar
  19. Giangiacomo, K. M., Kamassah, A., Harris, G., and McManus, O. B., 1998, Mechanism of maxi-K channel activation by dehydrosoyasaponin-I, J. Gen. Physiol. 112:485–501.PubMedCrossRefGoogle Scholar
  20. Gribkoff, V. K., Lum-Ragan, J. T., Boissard, C. G., Post-Munson, D. J., Meanwell, N. A., Starrett, J. E., Kozlowski, E. S., Romine, J. L., Trojnacki, J. T., McKay, M. C., Zhong, J., and Dworetzky, S. I., 1996, Effects of channel modulators on cloned large-conductance calcium-activated potassium channels, Mol. Pharmacol. 50:206–217.PubMedGoogle Scholar
  21. Hanner, M., Schmalhofer, W. A., Munujos, P., Knaus, H.-G., Kaczorowski, G. J., and Garcia, M. L., 1997, The β subunit of the high conductance calcium-activated potassium channel contributes to the high affinity receptor for charybdotoxin, Proc. Natl. Acad. Sci. U.S.A. 94:2853–2858.PubMedCrossRefGoogle Scholar
  22. Hanner, M., Vianna-Jorge, R., Kamassah, A., Schmalhofer, W. A., Knaus, H.-G., Kaczorowski, G. J., and Garcia, M. L., 1998, The β subunit of the high conductance calcium-activated potassium channel; identification of residues involved in charybdotoxin binding, J. Biol. Chem. 273:16289–16296.PubMedCrossRefGoogle Scholar
  23. Hewawasam, P., Meanwell, N. A., Gribkoff, V. K., Dworetzky, S. I., and Boissard, C. G., 1997, Discovery of a novel class of BK channel openers: Enantiospecific synthesis and BK channel opening activity of 3-(5-chloro-2-hydroxyphenyl)-l,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one,Bioorga. Medicinal Chem. Lett. 7:1255–1260.CrossRefGoogle Scholar
  24. Hu, S., Fink, C. A., Kim, H. S., and Lappe, R. W., 1997, Novel and potent BK channel openers: CGS 7181 and its analogs. Drug Dev. Res. 41:10–21.CrossRefGoogle Scholar
  25. Huang, J.-C., Garcia, M. L., Reuben, J. P., and Kaczorowski, G. J., 1993, Inhibition of β-adrenoceptor agonist relaxation of airway smooth muscle by Ca2+activated K+ channel blockers, Eur. J. Pharmacol. 235:37–43.PubMedCrossRefGoogle Scholar
  26. Johnson, B. A., and Sugg, E. E., 1992, Determination of the three-dimensional structure of iberiotoxin in solution by 1H nuclear magnetic resonance spectroscopy. Biochemistry 31:8151–8159.PubMedCrossRefGoogle Scholar
  27. Joiner, W. J., Tang, M. D., Wang, L.-Y., Dworetzky, S. I., Boissard, C. G., Gan, L., Gribkoff, V. K., and Kaczmarek, L. K., 1998, Formation of intermediate-conductance calcium-activated potassium channels by interaction of Slack and Slo subunits, Nat. Neurosci. 1:462–469.PubMedCrossRefGoogle Scholar
  28. Jones, T. R., Charette, L., Garcia, M. L., and Kaczorowski, G. J., 1990, Selective inhibition of relaxation of guinea-pig trachea by charybdotoxin, a potent Ca2+activated K+ channel inhibitor,J. Pharmacol. Exp. Ther. 255:697–705.PubMedGoogle Scholar
  29. Jones, T. R., Charette, M. L., Garcia, M. L., and Kaczorowski, G. J., 1993, Interaction of iberiotoxin with beta adrenoceptor agonists and sodium nitroprusside on guinea pig trachea, J. Appli. Physiol. 74:1879–1884.CrossRefGoogle Scholar
  30. Kaczorowski, G. J., Knaus, H.-G., Leonard, R. J., McManus, O. B., and Garcia, M. L., 1996, High conductance calcium-activated potassium channels; structure, pharmacology and function, J. Biomembr. Bioenerg. 28:255–267.CrossRefGoogle Scholar
  31. Knaus, H.-G., Eberhart, A., Kaczorowski, G. J., and Garcia, M. L., 1994a, Covalent attachment of charybdotoxin to the β-subunit of the high-conductance Ca2+-activated K+ channel,J. Biol. Chem. 269:23336–23341.PubMedGoogle Scholar
  32. Knaus, H.-G., Folander, K., Garcia-Calvo, M., Garcia, M. L., Kaczorowski, G. J., Smith, M., and Swanson, R., 1994b, Primary sequence and immunological characterization of the b-subunit of the high-conductance Ca2+-activated K+ channel from smooth muscle, J. Biol. Chem. 269:17274–17278.PubMedGoogle Scholar
  33. Knaus, H.-G., Garcia-Calvo, M., Kaczorowski, G. J., and Garcia, M. L., 1994c, Subunit composition of the high conductance calcium-activated potassium channel from smooth muscle, a representative of the mSlo and slowpoke family of potassium channels, J. Biol. Chem. 269:3921–3924.PubMedGoogle Scholar
  34. Knaus, H.-G., McManus, O. B., Lee, S. H., Schmalhofer, W. A., Garcia-Calvo, M., Helms, L. M. H., Sanchez, M., Giangiacomo, K., Reuben, J. P., Smith A. B., III Kaczorowski, G. J., and Garcia, M. L., 1994d, Tremorgenic indole alkaloids potently inhibit smooth muscle high-conductance Ca2+-activated K+ channels, Biochemistry 33:5819–5828.PubMedCrossRefGoogle Scholar
  35. Knaus, H.-G., Schwarzer, C., Koch, R. O. A., Eberhart, A., Kaczorowski, G. J., Glossmann, H., Wunder, F., Pongs, O., Garcia, M. L., and Sperk, G., 1996, Distribution of high-conductance Ca2+-activated K + channels in rat brain: Targeting to axons and nerve terminals, J. Neurosci. 16:955–963.PubMedGoogle Scholar
  36. Koch, R. O. A., Koschak, A., Wanner, S. G., Kaczorowski, G. J., Wittka, R., Garcia, M. L., and Knaus, H.-G., 1996, High-conductance calcium-activated potassium channels in rat brain: Pharmacological profile, quantification of expression, subunit composition and functional implications, Soc. Neurosci. Abstr. 22:1754.Google Scholar
  37. Koschak, A., Koch, R. O., Liu, J., Kaczorowski, G. J., Reinhart, P. H., Garcia, M. L., and Knaus, H.-G., 1997, [125I]Iberiotoxin-D19Y/Y36F, the first selective, high specific activity radioligand for high-conductance calcium-activated potassium channels. Biochemistry 36:1943–1952.PubMedCrossRefGoogle Scholar
  38. Kume, H., Tokuno, H., and Tomita, T., 1989, Regulation of Ca2+dependent K+-channels in trachael myocytes by phosphorylation, Nature 341:152–154.PubMedCrossRefGoogle Scholar
  39. Kume, H., Graziano, M. P., and Kotlikoff, M. I., 1992, Stimulatory and inhibitory regulation of calcium-activated potassium channels by guanine nucleotide-binding proteins,Proc. Natl. Acad. Sci. U.S.A. 89:11051–11055.PubMedCrossRefGoogle Scholar
  40. Latorre, R., Oberhauser, A., Labarca, P., and Alvarez, O., 1989, Varieties of calcium-activated potassium channels, Annu. Rev. Physiol. 51:385–399.PubMedCrossRefGoogle Scholar
  41. Li, Y., Starrett, J. E., Meanwell, N. A., Johnson, G., Harte, W. E., Dworetzky, S. I., Boissard, C. G., and Gribkoff, V. K., 1997, The discovery of novel openers of Ca2+dependent large-conductance potassium channels: Pharmacophore search and physiological evaluation of flavonoids,Bioorg, Medicinal Chem. Lett. 7:759–762.CrossRefGoogle Scholar
  42. MacKinnon, R., and Miller, C., 1988, Mechanism of charybdotoxin block of the high-conductance, Ca2+activated K+ channel, J. Gen. Physiol. 91:335–349.PubMedCrossRefGoogle Scholar
  43. MacKinnon, R., Latorre, R., and Miller, C., 1989, Role of surface electrostatics in the operation of a high-conductance Ca2+activated K+ channel, Biochemistry, 28:8092–8099.PubMedCrossRefGoogle Scholar
  44. McCobb, D. P., Fowler, N. L., Featherstone, T., Lingle, C. J., Saito, M., Krause, J. E., and Salkoff, L., 1995, A human calcium-activated potassium channel gene expressed in vascular smooth muscle, Am. J. Physiol. 269:H767–H777.Google Scholar
  45. McManus, O. B., 1991, Calcium-activated potassium channels: regulation by calcium, J. Bioenerg. Biomembr. 23:537–560.PubMedCrossRefGoogle Scholar
  46. McManus, O. B., Harris, G. H., Giangiacomo, K. M., Feigenbaum, P., Reuben, J. P., Addy, M. E., Burka, J. F., Kaczorowski, G. J., and Garcia, M. L., 1993, An activator of calcium-dependent potassium channels isolated from a medicinal herb. Biochemistry 32:6128–6133.PubMedCrossRefGoogle Scholar
  47. McManus, O. B., Helms, L. M. H., Pallanck, L., Ganetzky, B., Swanson, R., and Leonard, R. J., 1995, Functional role of the β subunit of high-conductance calcium-activated potassium channels. Neuron 14:1–20.CrossRefGoogle Scholar
  48. Meera, P., Wallner, M., Jiang, Z., and Toro, L., 1996, A calcium switch for the functional coupling between α (hslo) and β subunits (Kv#caβ) of maxi K channels, FEBS Lett. 382:84–88.PubMedCrossRefGoogle Scholar
  49. Meera, P., Wallner, M., Song, M., and Toro, L., 1997, Large conductance voltage- and calcium-dependent K+ channel, a distinct member of voltage-dependent ion channels with seven N-terminal transmembrane segments (S0-S6), an extracellular N terminus, and an intracellular (S9-S10) C terminus,Proc. Natl. Acad. Sci. U.S.A. 94:14066–14071.PubMedCrossRefGoogle Scholar
  50. Meera, P., Wallner, M., and Toro, L., 1999, Molecular determinant of maxi-K channel inactivation, Biophys. J. 76:A267.Google Scholar
  51. Miura, M., Belvesi, M. G., Stretton, C. D., Yacoub, M. H., and Barnes, P. J., 1992, Role of potassium channels in bronchodilator responses in human airways, Am. Rev. Respir. Dis. 146:132–136.PubMedGoogle Scholar
  52. Mullmann, T. J., Munujos, P., Garcia, M. L., and Giangiacomo, K. M., 1999, Electrostatic mutations in iberiotoxin as a unique tool for probing the electrostatic structure of the maxi-K channel outer vestibule, Biochemistry, 38:2395–2402PubMedCrossRefGoogle Scholar
  53. Munujos, P., Knaus, H.-G., Kaczorowski, G. J., and Garcia, M. L., 1995, Crosslinking of charybdotoxin to high-conductance calcium-activated potassium channels: Identification of the covalently modified toxin residue, Biochemistry 34:10771–10776.PubMedCrossRefGoogle Scholar
  54. Olesen, S.-P., 1994, Activators of large-conductance Ca2+-dependent K+ channels, Exp. Opin. Invest. Drugs 3:1181–1188.Google Scholar
  55. Olesen, S.-P., Munch, E., Moldt, P., and Drejer, J., 1994, Selective activation of Ca2+dependent K+ channels by novel benzimidazolone, Eur. J. Pharmacol. 251:53–59.PubMedCrossRefGoogle Scholar
  56. Pallanck, L., and Ganetzky, B., 1994, Cloning and characterization of human and mouse homologs of the Drosophila calcium-activated potassium channel gene, slowpoke, Hum. Mol. Genet. 3:1239–1243.CrossRefGoogle Scholar
  57. Park, C.-S., and Miller, C, 1992a, Interaction of charybdotoxin with permeant ions inside the pore of a K+ channel, Neuron 9:307–313.PubMedCrossRefGoogle Scholar
  58. Park, C.-S., and Miller, C, 1992b, Mapping function to structure in a channel-blocking peptide: Electrostatic mutants of charybdotoxin, Biochemistry 31:7749–7755.PubMedCrossRefGoogle Scholar
  59. Schreiber, M., and Salkoff, L., 1997, A novel calcium-sensing domain in the BK channel, Biophys. J. 73:1355–1363.PubMedCrossRefGoogle Scholar
  60. Shimony, E., Sun, T., Kolmakova-Partensky, L., and Miller, C, 1994, Engineering a uniquely reactive thiol into a cysteine-rich peptide,Protein Eng. 7:503–507.PubMedCrossRefGoogle Scholar
  61. Singh, S. B., Goetz, M. A., Zink, D. L., Dombrowski, A. W., Polishook, J. D., Garcia, M. L., Schmalhofer, W., McManus, O. B., and Kaczorowski, G. J., 1994, Maxikdiol: A novel dihydroxyisoprimane as an agonist of maxi-K channels, J. Chem. Soc., Perkin Trans. 1 1994:3349–3352.CrossRefGoogle Scholar
  62. Solaro, C. R., and Lingle, C. J., 1992, Trypsin-sensitive, rapid inactivation of a calcium-activated potassium channel,Science 257:1694–1698.PubMedCrossRefGoogle Scholar
  63. Stampe, P., Kolmakova-Partensky, L., and Miller, C, 1994, Intimations of K+ channel structure from a complete functional map of the molecular surface of charybdotoxin, Biochemistry 33:443–450.PubMedCrossRefGoogle Scholar
  64. Strobaek, D., Christophersen, P., Holm, N. R., Moldt, P., Ahring, P. K., Johansen, T. E., and Olesen, S.-P., 1996, Modulation of the Ca2+-dependent K+ channel, hslo, by the substituted diphenylurea NS 1608, paxilline and internal Ca2+, Neuropharmacology 35: 903–914.PubMedCrossRefGoogle Scholar
  65. Suarez-Kurtz, G., Garcia, M. L., and Kaczorowski, G. J., 1991, Effects of charybdotoxin and iberiotoxin on the spontaneous motility and tonus of different guinea pig smooth muscle tissues, J. Pharmacol. Exp. Ther. 259:439–443.PubMedGoogle Scholar
  66. Tanaka, Y., Meera, P., Song, M., Knaus, H.-G., and Toro, L., 1997, Molecular constituents of maxi KCa channels in human coronary smooth muscle: Predominant α+ β subunit complexes, J. Physiol. (London) 502:545–557.CrossRefGoogle Scholar
  67. Tseng-Crank, J., Foster, C. D., Krause, J. D., Mertz, R., Godinot, N., DiChiara, T. J., and Reinhart, P. H., 1994,Cloning, expression, and distribution of functionally distinct Ca2+-activated K+ channel isoforms from human brain, Neuron 13:1315–1330.PubMedCrossRefGoogle Scholar
  68. Tseng-Crank, J., Godinot, N., Johansen, T. E., Ahring, P. K., Strobaek, D., Mertz, R., Foster, C. D., Olesen,S.-P., and Reinhart, P. H., 1996, Cloning, expression, and distribution of a Ca2+-activated K+ channel β-subunit from human brain, Proc. Natl. Acad. Sci. U.S.A. 93:9200–9205.PubMedCrossRefGoogle Scholar
  69. Vazquez, J., Feigenbaum, P., Katz, G., King, V. F., Reuben, J. P., Roy-Contancin, L., Slaughter, R. S.,Kaczorowski, G. J., and Garcia, M. L., 1989, Characterization of high affinity binding sites for charybdotoxin in sarcolemmal membranes from bovine aortic smooth muscle: Evidence for a direct association with the high conductance calcium-activated potassium channel, J. Biol. Chem. 264:20902–20909.PubMedGoogle Scholar
  70. Vogalis, F., Vincent, T., Qureshi, I., Schmalz, F., Ward, M. W., Sanders, K. M., and Horowitz, B., 1996,Cloning and expression of the large-conductance Ca2+activated K+ channel from colonic smooth muscle, Am. J. Physiol. 271:G629–G639.Google Scholar
  71. Wallner, M., Meera, P., Ottolia, M., Kaczorowski, G. J., Latorre, R., Garcia, M. L., Stefani, E., and Toro, L., 1995,Characterization of and modulation by a β-subunit of a human maxi KCa channel cloned from myometrium, Recept. Channels 3:185–199.PubMedGoogle Scholar
  72. Wallner, M., Meera, P., and Toro, L., 1996, Determinant for β-subunit regulation in high-conductance voltage-activated and Ca2+-sensitive K+ channels: An additional transmembrane region at the N terminus,Proc. Natl. Acad. Sci. U.S.A. 93:14922–14927.PubMedCrossRefGoogle Scholar
  73. Wallner, M., Meera, P., and Toro, L., 1999, A novel β subunit leads to inactivating maxiK currents, Biophys. J. 76:A267.Google Scholar
  74. Wei, A., Jegla, T., and Salkoff, L., 1996, Eight potassium channel families revealed by the C. elegans genome project, Neuropharmacology 35:805–829.PubMedCrossRefGoogle Scholar
  75. Winquist, R. J., Heany, L. A., Wallace, A. A., Baskin, E. P., Stein, R. B., Garcia, M. L., and Kaczorowski, G., 1989, Glyburide blocks the relaxation response to BRL 34915 (cromakalim), minoxidil sulfate and diazoxide in vascular smooth muscle,J. Pharmacol. Exp. Ther. 248:149–156.PubMedGoogle Scholar
  76. Yao, Y., Peter, A. B., Baur, R., and Sigel, E., 1989, The tremorigen aflatrem is a positive allosteric modulator of the γ-amonibutyric acidA receptor channel expressed in Xenopus oocytes,Mol. Pharmacol. 35:319–323.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Maria L. Garcia
    • 1
  • Gregory J. Kaczorowski
    • 1
  1. 1.Membrane Biochemistry and BiophysicsMerck Research LaboratoriesRahwayUSA

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