Development and Regulation of Cardiac Muscarinic Acetylcholine Receptor Number, Function and Gyanyl Nucleotide Sensitivity

  • Stan W. Halvorsen
  • Bronia Engel
  • Dale D. Hunter
  • Neil M. Nathanson
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 161)


Acetylcholine is released from parasympathetic nerve terminals and binds to muscarinic acetylcholine (mACh) receptors to elicit negative chronotropic and inotropic effects on the heart. The molecular mechanisms for these cardiac effects are not well understood. Investigation of the mACh receptor has been greatly facilitated by the development of the potent cholinergic antagonist [3H] quinuclidinyl benzilate (QNB) which binds specifically and with high affinity to the mACh receptor (1). [3H]QNB can be used to study the interaction of agonists and antagonists with the receptor and quantitate the number of receptors present in cells and tissues.


Adenylate Cyclase Muscarinic Receptor Adenylate Cyclase Activity Receptor Number Muscarinic Acetylcholine Receptor 
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  1. 1.
    Yamamura, H.I. and Snyder, S.H. Muscarinic cholinergic binding in rat brain. Proceedings of the National Academy of Sciences USA 71, 1725–1729 (1974).CrossRefGoogle Scholar
  2. 2.
    Klein, W.L., Nathanson, N.M., and Nirenberg, M. Muscarinic acetylcholine receptor regulation by accelerated rate of receptor loss. Biochemical and Biophysical Research Communications 90, 506–512 (1979).PubMedCrossRefGoogle Scholar
  3. 3.
    Nathanson, N.M., Klein, W.L., and Nirenberg, M. Regulation of adenylate cyclase activity mediated by muscarinic acetylcholine receptors. Proceedings of the National Academy of Sciences USA 75, 1788–1791 (1978).CrossRefGoogle Scholar
  4. 4.
    Siman, R.G. and Klein, W.L. Specificity of muscarinic acetylcholine receptor regulation by receptor activity. Journal of Neurochemistry 37, 1099–1108 (1981).PubMedCrossRefGoogle Scholar
  5. 5.
    Galper, J.B. and Smith, T.W. Properties of muscarinic acetylcholine receptors in heart cell cultures. Proceedings of the National Academy of Sciences USA 75, 5831–5835 (1978).CrossRefGoogle Scholar
  6. 6.
    Taylor, J.E., El-Fakahany, E., and Richelson, E. Long-term regulation of muscarinic acetylcholine receptors on cultured nerve cells. Life Sciences 25, 2181–2187 (1979).PubMedCrossRefGoogle Scholar
  7. 7.
    Meyer, M.R., Gainer, M.W., and Nathanson, N.M. In vivo regulation of muscarinic cholinergic receptors in embryonic chick brain. Molecular Pharmacology 21, 280–286 (1982).PubMedGoogle Scholar
  8. 8.
    Marks, M.J., Artman, L.D., Patinkin, D.M. and Collins, A.C. Cholinergic adaptations to chronic oxotremorine infusion. Journal of Pharmacology and Experimental Therapeutics 218, 337–343 (1981).PubMedGoogle Scholar
  9. 9.
    Pappano, A.J. and Skowronek, C.A. Reactivity of chick embryo heart to cholinergic agonists during ontogenesis: decline in desensitization at the onset of cholinergic transmission. The Journal of Pharmacology and Experimental Therapeutics 191, 109–118 (1974).PubMedGoogle Scholar
  10. 10.
    Galper, J.B., Klein, W., and Catterall, W.A. Muscarinic acetycholine receptors in developing chick heart. The Journal of Biological Chemistry 252, 8692–8699 (1977).PubMedGoogle Scholar
  11. 11.
    Renaud, J.F., Barhanin, J., Cavey, D., Fosset, M. and Lazdunski, M. Comparative Properties of the in ovo and in vitro differentiation of the muscarinic cholinergic receptor in embryonic heart cells. Developmental Biology 78, 184–200 (1980).PubMedCrossRefGoogle Scholar
  12. 12.
    Pappano, A.J. Ontogenetic development of autonomic neuroeffector transmission and transmitter reactivity in embryonic and fetal hearts. Pharmacological Reviews 29, 3–33 (1977).PubMedGoogle Scholar
  13. 13.
    Pappano, A.J., Loffelholz, K. Ontogenesis of adrenergic and cholinergic neuroeffector transmission in chick embryo heart. The Journal of Pharmacology and Experimental Therapeutics 191, 468–478 (1974).PubMedGoogle Scholar
  14. 14.
    Murad, F., Chi, Y.-M., Rall, T.W., and Sutherland, E.W. Adenyl cyclase. Journal of Biological Chemistry 237, 1233–1238 (1962).PubMedGoogle Scholar
  15. 15.
    Jakobs, K.H., Aktories, K. and Schultz, G. GTP-dependent inhibition of cardiac adenylate cyclase by muscarinic cholinergic agonists. Naunyn-Schmiedeberg’s Archives Pharmacology 310, 113–119 (1979).CrossRefGoogle Scholar
  16. 16.
    Watanabe, A.M., McConnaughey, M.M., Strawbridge, R.Z., Fleming, J.W., Jones, L.R., and Besch, H.R. Jr. Muscarinic cholinergic receptor modulation of oradernergic receptor affinity for catecholamines. The Journal of Biological Chemistry 253, 4833–4836 (1978).PubMedGoogle Scholar
  17. 17.
    Rodbell, M. The role of hormone receptors and GTP-regulatory proteins in membrane transduction. Nature (London) 284, 17–22 (1980).CrossRefGoogle Scholar
  18. 18.
    Hoffman, B.B., Yim, S., Tsai, B.S. and Lefkowitz, R.J. Preferential uncoupling by manganese of alpha adrenergic receptor mediated inhibition of adenylate cyclase in human platelets. Biochemical and Biophysical Research Communications 100, 724–731 (1981).PubMedCrossRefGoogle Scholar
  19. 19.
    Koski, G. and Klee, W.A. Opiates inhibit adenylate cyclase by stimulating GTP hydrolysis. Proceedings of the National Academy of Sciences USA 78, 4185–4189 (1981).CrossRefGoogle Scholar
  20. 20.
    Berrie, C.P., Birdsall, N.J.M., Burgen, A.S.V. and Hulme, E.C. Guanine nucleotides modulate muscarinic receptor binding in the heart. Biochemical and Biophysical Research Communications 87,1000–1005 (1979).PubMedCrossRefGoogle Scholar
  21. 21.
    Rosenberger, L.B., Yamamura, H.I. and Roeske, W.R. Cardiac muscarinic cholinergic receptor binding is regulated by Na+ and guanyl nucleotides. The Journal of Biological Chemistry 255, 820–823 (1980).PubMedGoogle Scholar
  22. 22.
    Wei, J.-W. and Sulakhe, P.V. Requirement for sulfhydryl groups in the differential effects of magnesium ion and GTP on agonist binding of muscarinic cholinergic receptor sites in rat atrial membrane fraction. Naunynm-Schmiedeberg’s Archves Pharmacology 314, 51–59 (1980).CrossRefGoogle Scholar
  23. 23.
    Galper, J.B., and Smith, T.W. Agonist and guanine nucleotide modulation of muscarinic cholinergic receptors in cultured heart cells. The Journal of Biological Chemistry 255, 9571–9579 (1980).PubMedGoogle Scholar
  24. 24.
    Halvorsen, S.W. and Nathanson, N.M. In vivo regulation of muscarinic acetylcholine receptor number and function in embryonic chick heart. Journal of Biological Chemistry 256, 7941–7948 (1981).PubMedGoogle Scholar
  25. 25.
    Northup, J.K., Sternweis, P.C., Smigel, M.D., Schleiffer, L.S., Ross, E.M. and Gilman, A.G. Purification of the regulatory component of adenylate cyclase. Proceedings of the National Academy of Sciences USA 77, 6516–6520 (1980).CrossRefGoogle Scholar
  26. 26.
    Hamburger, V. and Hamilton, H.L. A series of normal stages in the development of the chick embryo. Journal of Morphology 88, 49–92 (1951).CrossRefGoogle Scholar
  27. 27.
    Halvorsen, S.W. and Nathanson, N.M. Ontogenesis of physiological responsiveness and guanyl nucleotide sensitivity of cardiac muscarinic receptors during chick embryonic development. Manuscript submitted for publication.Google Scholar
  28. 28.
    McKnight, G.S. A colorimetric method for the determination of submicrogram quantities of protein. Analytical Biochemistry 78, 86–92 (1977).PubMedCrossRefGoogle Scholar
  29. 29.
    Lowry, O.H., Rosebrough, N.J., Farr, A.L., and Randall, R.J. Protein measurement with Folin phenol reagent. Journal of Biological Chemistry 193, 265–275 (1951).PubMedGoogle Scholar
  30. 30.
    Salomon, Y., Londos, C., and Rodbell, M. A highly sensitive adenylate cyclase assay. Analytical Biochemistry 58, 541–548 (1974).PubMedCrossRefGoogle Scholar
  31. 31.
    Birdsall, N.J.M., Burgen, A.S.U. and Hulme, E.C. The binding of agonists to brain muscarinic receptors. Molecular Pharmacology 14, 723–736 (1978).PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1983

Authors and Affiliations

  • Stan W. Halvorsen
    • 1
  • Bronia Engel
    • 1
  • Dale D. Hunter
    • 1
  • Neil M. Nathanson
    • 1
  1. 1.Department of PharmacologyUniversity of WashingtonSeattleUSA

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