Advertisement

Molecular and Cellular Biochemistry

, Volume 33, Issue 1–2, pp 67–92 | Cite as

Adenylate cyclase: The role of magnesium and other divalent cations

  • Stella Y. Cech
  • William C. Broaddus
  • Michael E. Maguire
Article

Summary

While it is now well-established that guanine nucleotide is an important regulatory agent acting on the hormone receptor-adenylate cyclase complex, only recently has sufficient evidence accumulated to indicate that free divalent cation, particularly free Mg2+, is also an important modulatory ligand. This review discusses the interactions of free divalent cation with the receptor-cyclase complex with regard to mechanism and site of action of metal ions, receptor-mediated inhibition of Mg2+ transport, and physiological function of the Mg2+ interactions.

Careful kinetic analyses indicate that the receptor-cyclase complex possesses specific sites for free Mg2+. The influence of Mg2+ on these sites is demonstrated by a Mg2+-induced increase in both agonist affinity for the hormone receptor and Vmax of adenylate cyclase catalytic activity, without change in Km for the MgATP2− substrate. Upon addition of guanine nucleotide, the effect of free Mg2+ on agonist affinity for the receptor is abolished. However, the coupling influence of nucleotide or of nucleotide plus hormone does not eliminate increased catalytic activity induced by Mg2+, but appears to increase the apparent affinity of free Mg2+ for its binding site(s). Data from specific mutant cell lines of the murine S49 lymphoma and from solubilization and reconstitution studies with S49 cells and turkey and frog erythrocytes indicate that both free Mg2+ and guanine nucleotide interact with the guanine nucleotide coupling protein at the cytoplasmic membrane face.

The roles of Mn2+ and Ca2+ are less well-studied. Our assessment of published data suggests that neither of these cations is a major regulatory ligand of receptor-cyclase function. Ca2+ interacts weakly if at all with free Mg2+ sites, and the CaATP2− complex, while probably a nonproductive substrate, is a poor competitive inhibitor of the enzyme. Some evidence indicates that Ca2+ plus the Ca2+-dependent regulatory protein (calmodulin) has a potential modulatory role for a subclass of nervous system receptor-cyclase complexes. The significance of this interaction is not clear. Mn2+, unlike Ca2+, forms a productive substrate complex and in addition appears to interact with the free Mg2+ site(s). However, in contrast to the activation produced by free Mg2+, Mn2+ may be an inhibitory cation at the free metal site(s). However, no physiological significance of these interactions with Mn2+ is known.

Further complexity has been added to the interactions of Mg2+ with the receptor-cyclase complex by this laboratory's description of hormonal inhibition of Mg2+ transport across the plasma membrane. Using mutant cell clones of the S49 lymphoma cell we have been able to show that this inhibition of Mg2+ transport is not mediated by cyclic AMP. The transport function appears to be a property of the receptor-cyclase complex itself or of a possible Mg2+ transport protein associated with the hormone receptor. The potential physiological significance of hormone-sensitive Mg2+ transport is discussed.

Finally, we suggest, as a framework for future experimentation, a sequence of interactions of Mg2+, GTP and hormone with the receptor-cyclase complex that appears to account for the effect of and interactions between these regulatory ligands. Specifically, we suggest that activation of adenylate cyclase by hormone occurs via, a form of the receptor-cyclase complex induced by and absolutely requiring the presence of bound Mg2+. Furthermore, formation of this complex requires the absence of bound GTP. Subsequent interaction of this Mg+-containing complex with GTP results in activation of the cyclase catalytic component. We further suggest that reported differences in Mg2+/GTP interactions on receptor-cyclase complexes from different cell types are a function of minor differences (e.g. in ligand affinities) in the same fundamental characteristics. The mechanism of hormonal activation of the receptor-cyclase complex appears to be identical regardless of species or cell type and in all cases appears to require interaction with both free Mg2+ and guanine nucleotide. In this regard, it should be noted that the nucleotide coupling protein is more properly described as a metal/nucleotide coupling protein.

Keywords

Adenylate Cyclase Guanine Nucleotide Mutant Cell Line Modulative Ligand Agonist Affinity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Maguire, M. E., Van Arsdale, P. M. and Gilman, A. G., 1976. Mol. Pharmacol. 12, 335–339.Google Scholar
  2. 2.
    Lefkowitz, R. J., Mullikin, D. and Caron, M. G., 1976. J. Biol. Chem. 251, 4686–4692.Google Scholar
  3. 3.
    Maguire, M. E., Ross, E. M. and Gilman, A. G., 1977. Adv. Cyclic Nucleotide Res. 8 (Greengard, P. and Robison, G. A., eds.), pp. 1–83, Raven Press, New York, New York.Google Scholar
  4. 4.
    Haga, T., Haga, K. and Gilman, A. G., 1977. J. Biol. Chem. 252, 5767–5782.Google Scholar
  5. 5.
    Ross, E. M., Howlett, A. C., Ferguson, K. M. and Gilman, A. G., 1978. J. Biol. Chem. 253, 6401–6412.Google Scholar
  6. 6.
    Ross, E. M. and Gilman, A. G., 1977. J. Biol. Chem. 252, 6966–6969.Google Scholar
  7. 7.
    Daniel, V., Litwack, G. and Tomkins, G. M., 1973. Proc. Nat. Acad. Sci U.S.A. 70, 76–97.Google Scholar
  8. 8.
    Coffino, P., Bourne, H. R. and Tomkins, G. M., 1975. J. Cell. Physiol. 85, 603–610.Google Scholar
  9. 9.
    Bourne, H. R., Coffino, P. and Tomkins, G. M., 1975. J. Cell. Physiol. 85, 611–620.Google Scholar
  10. 10.
    Bird, S. J. and Maguire, M. E., 1978. J. Biol. Chem. 153, 8826–8834.Google Scholar
  11. 11.
    Maguire, M. E. and Erdos, J. J., 1978. J. Biol. Chem. 253, 6633–6636.Google Scholar
  12. 12.
    Johnson, G. L., Bourne, H. R., Gleason, M. K., Coffino, P., Insel, P. A. and Melmon, K. L., 1979. Mol. Pharmacol. 15, 16–27.Google Scholar
  13. 13.
    Johnson, G. L., Kaslow, H. R. and Bourne, H. R., 1978. Proc. Nat. Acad. Sci. U.S.A., 75, 3113–3117.Google Scholar
  14. 14.
    Johnson, G. L., Bourne, H. R., Gleason, M. K., Coffino, P., Insel, P. A. and Melmon, K. L., 1979. Mol. Pharmacol. 15, 16–27.Google Scholar
  15. 15.
    Haga, T., Ross, E. M., Anderson, H. J. and Gilman, A. G., 1977. Proc. Nat. Acad. Sci. U.S.A. 74, 2016–2020.Google Scholar
  16. 16.
    Sternweis, P. C. and Gilman, A. G., 1979. J. Biol. Chem. 254, 3333–3340.Google Scholar
  17. 17.
    Maguire, M. E. and Erdos, J. J., 1980. J. Biol. Chem. 255, 1030–1035.Google Scholar
  18. 18.
    Schleifer, L. S., Garrison, J. C., Sternweis, P. C., Northup, J. K. and Gilman, A. G., 1980. J. Biol. Chem. 255, 2641–2644.Google Scholar
  19. 19.
    Bourne, H. R., Coffino, P. and Tomkins, G. M., 1975. Science 187, 750–751.Google Scholar
  20. 20.
    Insel, P. A., Maguire, M. E., Gilman, A. G., Bourne, H. R., Coffino, P. and Melmon, K. L., 1976. Mol. Pharmacol. 12, 1062–1069.Google Scholar
  21. 21.
    Ross, E. M., Maguire, M. E., Sturgill, T. W., Biltonen, R. L. and Gilman, A. G., 1977. J. Biol. Chem. 252, 5761–5775.Google Scholar
  22. 22.
    Insel, P., Bourne, H. R., Coffino, P. and Tomkins, G. M., 1975. Science 190, 896–898.Google Scholar
  23. 23.
    Insel, P. and Fenno, J., 1978. Proc. Nat. Acad. Sci. U.S.A. 75, 862–865.Google Scholar
  24. 24.
    Steinberg, R. A., van Daalen Wetters, T. and Coffino, P., 1978. Cell 15, 1351–1361.Google Scholar
  25. 25.
    Maguire, M. E., Wikland, R. A., Anderson, H. J. and Gilman, A. G., 1976. J. Biol. Chem. 251, 1221–1231.Google Scholar
  26. 26.
    Rall, T. W. and Sutherland, E. W., 1958. J. Biol. Chem. 232, 1065–1076.Google Scholar
  27. 27.
    Perkins, J. P., 1973. Adv. Cyclic Nucleotide Res. 3 (Greengard, P. and Robison, G. A., eds.), pp. 1–64, Raven Press, New York, New York.Google Scholar
  28. 28.
    Birnbaumer, L., Pohl, S. L. and Rodbell, M., 1969, J. Biol. Chem. 244, 3468–3476.Google Scholar
  29. 29.
    Drummond, G. I. and Duncan, L., 1970. J. Biol. Chem. 245, 976–983.Google Scholar
  30. 30.
    Drummond, G. I., Severson, D. L. and Duncan, L., 1971. J. Biol. Chem. 246, 4166–4173.Google Scholar
  31. 31.
    DeHäen, C., 1974. J. Biol. Chem. 249, 2756–2762.Google Scholar
  32. 32.
    Salomon, Y., Lin, M. C., Londos, C., Rendell, M., and Rodbell, M., 1975. J. Biol. Chem. 250, 4239–4245.Google Scholar
  33. 33.
    Lin, M. C., Salomon, Y., Rendell, M., and Rodbell, M., 1975. J. Biol. Chem. 250, 4246–4252.Google Scholar
  34. 34.
    Rendell, M., Salomon, Y., Lin, M. C., Rodbell, M. and Berman, M., 1975. J. Biol. Chem. 250, 4253–4260.Google Scholar
  35. 35.
    Rodbell, M., 1975. J. Biol. Chem. 250, 5826–5834.Google Scholar
  36. 36.
    Hammes, G. G. and Rodbell, M., 1976. Proc. Nat. Acad. Sci. U.S.A. 73, 1189–1192.Google Scholar
  37. 37.
    Garbers, D. L. and Johnson, R. A., 1975. J. Biol. Chem. 250, 8449–8456.Google Scholar
  38. 38.
    Londos, C. and Preston, M. S., 1977. J. Biol. Chem. 252, 5957–5961.Google Scholar
  39. 39.
    Narayanan, N. and Sulakhe, P. V., 1977. Mol. Pharmacol. 13, 1033–1047.Google Scholar
  40. 40.
    Narayanan, N. and Sulakhe, P. V., 1978. Arch. Biochem. Biophys. 185, 72–81.Google Scholar
  41. 41.
    Wei, J.-W., Narayanan, N. and Sulakhe, P. V., 1979. Int. J. Biochem. 10, 109–116.Google Scholar
  42. 42.
    Narayanan, N., Wei, J.-W. and Sulakhe, P. V., 1979. Arch. Biochem. Biophys. 197, 18–29.Google Scholar
  43. 43.
    Rodan, S. B., Golub, E. E., Egan, J. J. and Rodan, G. A., 1980. Biochem. J. 185, 629–637.Google Scholar
  44. 44.
    Jakobs, K. H., Saur, W. and Schultz, G., 1978. Mol. Pharmacol. 14, 1073–1078.Google Scholar
  45. 45.
    Johnson, R. A., Sant, W. and Jakobs, K. H., 1979. J. Biol. Chem. 254, 1094–1101.Google Scholar
  46. 46.
    Harris, R. H., Cruz, R. and Bennun, A., 1979. BioSystems 11, 29–46.Google Scholar
  47. 47.
    Kanof, P. D., Hegstrand, L. R. and Greengard, P., 1977. Arch. Biochem. Biophys. 182, 321–334.Google Scholar
  48. 48.
    Premont, J., Guillon, G. and Bockaert, J., 1979. Biochem. Biophys. Res. Comm. 90, 513–519.Google Scholar
  49. 49.
    Torres, H. N., Flawiá, M. M., Medrano, J. A. and Cuatrecasas, P., 1978. J. Memb. Biol. 43, 19–44.Google Scholar
  50. 50.
    Lefkowitz, R. J., 1974. J. Biol. Chem. 249, 6119–6124.Google Scholar
  51. 51.
    Lefkowitz, R. J. and Caron, M. G., 1975. J. Biol. Chem. 250, 4418–4422.Google Scholar
  52. 52.
    Alvarez, R. and Bruno, J. J., 1977. Proc. Nat. Acad. Sci U.S.A. 74, 92–95.Google Scholar
  53. 53.
    Drummond, G. I. and Dunham, J., 1978. Arch. Biochem. Biophys. 189, 63–75.Google Scholar
  54. 54.
    Snyder, F. F. and Drummond, G. I., 1978. Arch. Biochem. Biophys. 185, 116–125.Google Scholar
  55. 55.
    Johnson, R. A. and Sutherland, E. W., 1973. J. Biol. Chem. 248, 5114–5121.Google Scholar
  56. 56.
    Hanski, E., Sevilla, N. and Levitski, A., 1977. For. J. Biochem. 76, 513–520.Google Scholar
  57. 57.
    Burke, G., 1970. Biochim. Biophys. Acta. 220, 30–41.Google Scholar
  58. 58.
    Blume, A. J. and Foster, C. J., 1976. J. Neurochem. 26, 305–311.Google Scholar
  59. 59.
    Fain, J. N. and Malbon, C. C., 1979. Mol. Cell. Biochem. 25, 143–169.Google Scholar
  60. 60.
    Flawiá, M. M. and Torres, H. N., 1972. J. Biol. Chem. 247, 6880–6883.Google Scholar
  61. 61.
    Paveto, C., Epstein, A., and Passaron, S., 1975. Arch. Biochem. Biophys. 169, 449–457.Google Scholar
  62. 62.
    Franco de Silviera, J., Zingales, B., and Colli, W., 1977. Biochim. Biophys. Acta 481, 722–733.Google Scholar
  63. 63.
    Gomes, S. L. and Maia, J. C. C., 1979. Biochim. Biophys. Acta 457, 257–264.Google Scholar
  64. 64.
    Braun, T. and Dods, R. F., 1975. Proc. Nat. Acad. Sci. U.S.A. 72, 1097–1101.Google Scholar
  65. 65.
    Braun, T., Frank, H., Dods, R. and Sepsenwol, S., 1977. Biochim. Biophys. Acta 481, 227–235.Google Scholar
  66. 66.
    Neer, E. J., 1978. J. Biol. Chem. 253, 5808–5812.Google Scholar
  67. 67.
    Naya-Vigne, J., Johnson, G. L., Bourne, H. R. and Coffino, P., 1978. Nature 272, 720–722.Google Scholar
  68. 68.
    Londos, C., Lad, P. M., Nielson, T. B. and Rodbell, M., 1979. J. Supramol. Struc. 10, 459–465.Google Scholar
  69. 69.
    Neer, E. J., 1979. J. Biol. Chem. 254, 2089–2096.Google Scholar
  70. 70.
    Limbird, L. E., Hickey, A. R. and Lefkowitz, R. J., 1979. J. Biol. Chem. 254, 2677–2683.Google Scholar
  71. 71.
    Goldberg, N. D. and Haddox, M. K., 1977. Ann. Rev. Biochem. 46, 823–896.Google Scholar
  72. 72.
    Murad, F., Mittal, C. K., Arnold, W. P., Katsuki, S. and Kimura, H., 1974. Adv. Cyclic Nucleotide Res. 9 (George, W. J. and Ignarro, L. J., eds.), pp. 145–158, Raven Press, New York, New York.Google Scholar
  73. 73.
    Bradham, L. S., Holt, D. A. and Sims, M., 1970. Biochim. Biophys. Acta 201, 250–260.Google Scholar
  74. 74.
    Brostrom, C. O., Huang, Y. C., Breckenridge, B. McL. and Wolff, D. J., 1975. Proc. Nat. Acad. Sci. U.S.A. 72, 64–68.Google Scholar
  75. 75.
    Cheung, W. Y., Bradham, L. S., Lynch, T. J., Lin, Y. M. and Tallant, E. A., 1975. Biochem. Biophys. Res. Commun. 66, 1055–1062.Google Scholar
  76. 76.
    Brostrom, M. A., Brostrom, C. O., Breckenridge, B. McL. and Wolff, D. J., 1976. J. Biol. Chem. 251, 4744–4750.Google Scholar
  77. 77.
    Brostrom, M. A., Brostrom, C. O., Breckenridge, B. McL. and Wolff, D. J., 1978. Adv. Cyclic Nucleotide Res. 9 (Greengard, P. and Robison, G. A., eds.), pp. 85–99, Raven Press, New York, New York.Google Scholar
  78. 78.
    Brostrom, M. A., Brostrom, C. O. and Wolff, D. J., 1978. Arch. Biochem. Biophys. 191, 341–350.Google Scholar
  79. 79.
    Lynch, T. J., Tallant, E. A. and Cheung, W. Y., 1977. Arch. Biochem. Biophys. 182, 124–133.Google Scholar
  80. 80.
    Wolff, D. J. and Brostrom, C. O., 1979. Adv. Cyclic Nucleotide Res. 11 (Greengard, P. and Robison, G. A., eds.). pp. 27–88 Raven Press, New York, New York.Google Scholar
  81. 81.
    Burgess, W. H., Howlett, A. C., Kretsinger, R. H. and Gilman, A. G., 1978. J. Cyclic Nucleotide Res. 4, 175–181.Google Scholar
  82. 82.
    Waterson, D. M., Harrelson, W. G., Keller, P. M., Sharief, F. and Vanaman, T. C., 1976. J. Biol. Chem. 251, 4501–4513.Google Scholar
  83. 83.
    MacDonald, I. A., 1975. Biochem. Biophys. Acta 397, 244–253.Google Scholar
  84. 84.
    Pohl, S. L., Birnbaumer, L. and Rodbell, M., 1971. J. Biol. Chem. 246, 1849–1856.Google Scholar
  85. 85.
    Steer, M. L. and Levitski, A., 1975. J. Biol. Chem. 250, 2080–2084.Google Scholar
  86. 86.
    Steer, M. and Levitski, A., 1975. Arch. Biochem. Biophys. 167, 371–376.Google Scholar
  87. 87.
    Chapman, D. B. and Way, E. L., 1980. Ann. Rev. Pharmacol. Toxicol. 20, 553–579.Google Scholar
  88. 88.
    Williams, L. T., Mullikin, D. and Lefkowitz, R. J., 1978. J. Biol. Chem., 253, 2984–2989.Google Scholar
  89. 89.
    Vauquelin, G., Bottari, S. and Strosberg, A. D., 1980. Mol. Pharmacol. 17, 163–171.Google Scholar
  90. 90.
    Vauquelin, G. and Maguire, M. E., 1980. Submitted for publication.Google Scholar
  91. 91.
    Tsai, B. S. and Lefkowitz, R. J., 1978. Mol. Pharmacol. 14, 540–548.Google Scholar
  92. 92.
    Tsai, B. S. and Lefkowitz, R. J., 1979. Mol. Pharmacol. 16, 61–68.Google Scholar
  93. 93.
    Rouot, B. M., U'Prichard, D. C. and Snyder, S. H., 1980, J. Neurochem. 34, 374–384.Google Scholar
  94. 94.
    U'Prichard, D. C. and Snyder, S. H., 1980. J. Neurochem., 34, 385–394.Google Scholar
  95. 95.
    Pearlmutter, A. F. and Soloff, M. S., 1979. J. Biol. Chem. 254, 3899–3906.Google Scholar
  96. 96.
    Erdos, J. J. and Maguire, M. E., 1980. Mol. Pharmacol., in press.Google Scholar
  97. 97.
    Dickson, P., 1979. The Official Rule Book, Delacorte Press, New York, New York.Google Scholar
  98. 98.
    Cassel, D. and Selinger, Z., 1976. Biochim. Biophys. Acta. 452, 538–551.Google Scholar
  99. 99.
    Cassel, D., Levkovitz, H. and Selinger, Z., 1977. J. Cyclic Nucleotide Res. 3, 393–406.Google Scholar
  100. 100.
    Kent, R. S., DeLean, A. and Lefkowitz, R. J., 1980. Mol. Pharmacol. 17, 14–23.Google Scholar
  101. 101.
    Stadel, J. M., DeLean, A. and Lefkowitz, R. J., 1980. J. Biol. Chem. 255, 1436–1441.Google Scholar
  102. 102.
    Limbird, L. E. and Lefkowitz, R. J., 1978. Proc. Nat. Acad. Sci. U.S.A. 75, 228–232.Google Scholar
  103. 103.
    Limbird, L. E., Hickey, A. R. and Lefkowitz, R. J., 1979. J. Cyclic Nucleotide Res. 5, 251–255.Google Scholar
  104. 104.
    Limbird, L. E., Gill, M. G., Stadel, J. M., Hickey, A. R. and Levkovitz, R. J., 1980. J. Biol. Chem. 255, 1854–1861.Google Scholar
  105. 105.
    Welton, A. F., Lad, P. M., Newby, A. C., Yamamura, H., Nicosia, S. and Rodbell, M., 1977. J. Biol. Chem. 252, 5947–5950.Google Scholar
  106. 106.
    Schlegel, W., Kempner, E. S. and Rodbell, M., 1979. J. Biol. Chem. 254, 5168–5176.Google Scholar
  107. 107.
    Howlett, A. C., Sternweis, P. C., Macik, B. A., Van Arsdale, P. M. and Gilman, A. G., 1979. J. Biol. Chem. 254, 2287–2295.Google Scholar
  108. 108.
    Caron, M. G., Limbird, L. E. and Lefkowitz, R. J., 1979. Mol. Cell. Biochem. 28, 45–66.Google Scholar
  109. 109.
    Cassel, D. and Selinger, Z., 1978. Proc. Nat. Acad. Sci U.S.A. 75, 4155–4159.Google Scholar
  110. 110.
    Spiegel, A. M., Brown, E. M., Fedak, S. A., Woodard, C. J. and Aurbach, G. D., 1976. J. Cyclic Nucleotide Res. 2, 47–56.Google Scholar
  111. 111.
    Salomon, Y., Lin, M. C., Londos, C., Rendell, M. and Rodbell, M., 1975. J. Biol. Chem. 250, 4239–4245.Google Scholar
  112. 112.
    Jacobs, S., Bennett, V. and Cuatrecasas, P., 1976. J. Cyclic Nucleotide Res. 2, 205–223.Google Scholar
  113. 113.
    Lad, P. M., Nielsen, T. B., Preston, M. S. and Rodbell, M., 1980. J. Biol. Chem. 256, 988–995.Google Scholar
  114. 114.
    Pfeuffer, T., 1977. J. Biol. Chem. 252, 7224–7234.Google Scholar
  115. 115.
    Swillens, S., Juvent, M. and Dumont, J. E., 1979. FEBS Letters 108, 365–368.Google Scholar
  116. 116.
    Cassel, D. and Selinger, Z., 1978. Proc. Nat. Acad. Sci. U.S.A. 75, 4155–4159.Google Scholar
  117. 117.
    Cassel, D., Eckstein, F., Lowe, M. and Selinger, Z., 1979. J. Biol. Chem. 254, 9834–9838.Google Scholar
  118. 118.
    Eckstein, F., Cassel, D., Levkovitz, H., Lowe, M. and Selinger, Z., 1979. J. Biol. Chem. 254, 9829–9834.Google Scholar
  119. 119.
    Kimura, N. and Nagata, N., 1979. J. Biol. Chem. 254, 3451–3457.Google Scholar
  120. 120.
    Pfeuffer, T. and Helmreich, E. J. M., 1975. J. Biol. Chem. 250, 867–876.Google Scholar
  121. 121.
    Downs, R. W., Speigel, A. M., Singer, M., Reen, S. and Aurbach, G. D., 1980. J. Biol. Chem. 255, 949–954.Google Scholar
  122. 122.
    Bhat, M. K., Iyenger, R., Abramowitz, J. and Birnbaumer, L., 1980. Fed. Proc. 39, 516.Google Scholar
  123. 123.
    MacLennan, D. H., Yip, C. C., Iles, G. H. and Seeman, P., 1973. Cold Spring, Harbor Symp. Quant. Biol. 37, 469–477.Google Scholar
  124. 124.
    Racker, E. and Eytan, E., 1973. Biochem. Biophys. Res. Comm. 55, 174–178.Google Scholar
  125. 125.
    Parkinson, C. N., 1962. In-Laws and Outlaws, Houghton Mifflin, New York.Google Scholar

Copyright information

© Dr. W. Junk b.v. Publishers 1980

Authors and Affiliations

  • Stella Y. Cech
    • 1
  • William C. Broaddus
    • 1
  • Michael E. Maguire
    • 1
  1. 1.Department of Pharmacology, School of MedicineCase Western Reserve UniversityCleveland

Personalised recommendations