Mechanisms for Regulation of β-Adrenergic Receptor Function in Desensitization

  • R. J. Lefkowitz
Chapter

Abstract

The advent of direct radioligand binding studies of a variety of receptors over the past few years has made it possible to directly investigate the role of receptor alterations in mediating a variety of physiological changes in drug responsiveness. Among the more interesting properties of many biologically active agonist drugs is the fact that they not only stimulate target tissues but they also desensitize them. This means that after a period of agonist stimulation the response of the target tissue often wanes even in the continued presence of the agonist. Many terms have been used to describe these phenomena including desensitization, tolerance, tachyphylaxis and refractoriness. Desensitization is of interest to basic as well as clinical pharmacologists because it may be a major mechanism which limits the therapeutic effectiveness of various drugs. If one could understand the molecular basis for desensitization it might be possible to design therapeutic strategies to alter it. However, since only agonists desensitize tissues (antagonists do not), it seems likely that the activating and desensitizing properties of various agonists are very intimately linked. Thus, a very detailed understanding of these processes is likely to be necesary if they are to be dissected apart.

Keywords

Adenylate Cyclase Guanine Nucleotide Astrocytoma Cell Agonist Binding Heterologous Desensitization 
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.
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References

  1. Chuang, D. M. & Costa, E. (1979). Evidence for internalization of the recognition site of β-adrenergic receptors during receptor subsensitivity induced by (-)isoproterenol. Proc. Nat. Acad. Sci. USA, 76, 3024–3028.PubMedCentralCrossRefPubMedGoogle Scholar
  2. De Lean, A., Stadel, J. M. & Lefkowitz, R. J. (1980). A ternary complex model explains the agonist-specific binding properties of the adenylate-cyclase coupled β-adrenergic receptor. J. biol. Chem., 255, 7108–7117.PubMedGoogle Scholar
  3. Harden, T. K., Cotton, C. U., Waldo, G. L., Lutton, J. K. & Perkins, J. P. (1980). Catecholamine induced alteration in the sedimentation behavior of membrane bound β-adrenergic receptors. Science, in press.Google Scholar
  4. Kent, R. S., De Lean, A. & Lefkowitz, R. J. (1980). Quantitative analysis of β-adrenergic receptor interactions: resolution of high and low affinity states of the receptor by computer modelling of ligand binding data. Mol. Pharmac., 17, 14–23.Google Scholar
  5. Lefkowitz, R. J., Mullikin, D. & Caron, M. G. (1976). Regulation of β-adrenergic receptors by 5’guanylyl-imidodiphosphate and other purine nucleotides. J. biol. Chem., 251, 4686–4692.PubMedGoogle Scholar
  6. Lefkowitz, R. J., Wessels, M. & Stadel, J. (1980). Hormone receptors and cyclic AMP: Their role in target cell refractoriness. In Current Topics in Cellular Regulation, ed. Horecker, B. & Stadtman, E., in press.Google Scholar
  7. Lefkowitz, R. J. & Williams, L. T. (1977). Catecholamine binding to the β-adrenergic receptor. Proc. Nat. Acad. Sci. USA, 74, 515–519.PubMedCentralCrossRefPubMedGoogle Scholar
  8. Limbird, L. E., Gill, D. M. & Lefkowitz, R. J. (1980). Agonist promoted coupling of the β-adrenergic receptor with the guanine nucleotide regulatory protein. Proc. Nat. Acad. Sci. USA, 77, 775–779.PubMedCentralCrossRefPubMedGoogle Scholar
  9. Limbird, L. E., Gill, D. M., Stadel, J. M., Hickey, A. R. & Lefkowitz, R. J. (1980). Loss of β-adrenergic receptor-guanine nucleotide regulatory protein interactions accompanies decline in catecholamine responsiveness of adenylate cyclase in maturing rat erythrocytes. J. biol. Chem., 255, 1854–1861.PubMedGoogle Scholar
  10. Limbird, L. E., Hickey, A. & Lefkowitz, R. J. (1979). Unique uncoupling of the frog erythrocyte adenylate cyclase by manganese. J. biol. Chem., 254, 2677–2683.PubMedGoogle Scholar
  11. Limbird, L. E. & Lefkowitz, R. J. (1978). Agonist-induced increase in apparent β-adrenergic receptor size. Proc. Nat. Acad. Sci. USA, 75, 228–232.PubMedCentralCrossRefPubMedGoogle Scholar
  12. Mickey, J. V., Tate, R. & Lefkowitz, R. J. (1975). Subsensitivity of adenylate cyclase and decreased β-adrenergic receptor binding after chronic exposure to (-)isoproterenol in vitro. J. biol. Chem., 250, 5727–5729.PubMedGoogle Scholar
  13. Mickey, J. V., Tate, R., Mullikin, D. & Lefkowitz, R. J. (1976). Characterization of catecholamines tolerance in vitro: Correlation between adenylate cyclase sensitivity and β-adrenergic receptor binding. Mol. Pharmac., 12, 409–419.Google Scholar
  14. Mukherjee, C., Caron, M. G. & Lefkowitz, R. J. (1976). Regulation of β-adrenergic receptors by β-adrenergic agonists in vivo. Endocrinology, 99, 343–353.CrossRefGoogle Scholar
  15. Orly, J. & Schramm, M. (1976). Coupling of catecholamine receptor from one cell with adenylate cyclase from another cell by cell fusion. Proc. Nat. Acad. Sci. USA, 73, 4410–4414.PubMedCentralCrossRefPubMedGoogle Scholar
  16. Pike, L. J. & Lefkowitz, R. J. (1980). Use of cell fusion techniques to probe the mechanism of catecholamine-induced desensitization of adenylate cyclase in frog erythrocytes. Biochim. Biophys. Acta., in press.Google Scholar
  17. Stadel, J. M., De Lean, A. & Lefkowitz, R. J. (1980). A high affinity agonist-β-adrenergic receptor complex is an intermediate for catecholamine stimulation of adenylate cyclase in turkey and frog erythrocyte membranes. J. biol. Chem., 255, 1436–1441.PubMedGoogle Scholar
  18. Stadel, J. M. & Lefkowitz, R. J. (1979). Multiple reactive sulfhydryl groups modulate the function of adenylate cyclase coupled β-adrenergic receptors. Mol. Pharmac., 16, 709–718.Google Scholar
  19. Su, Y. F., Cubeddu, L. & Perkins, J. P. (1976). Regulation of adenosine 3′:5′-monophosphate content of human astrocytoma cells: desensitization to catecholamines and prostaglandins. J. cyclic Nucl. Res., 2, 257–270.Google Scholar
  20. Su, Y. F., Harden, T. K. & Perkins, J. P. (1979). Isoproterenol-induced desensitization of adenylate cyclase in human astrocytoma cells. J. biol. Chem., 254, 38–44.PubMedGoogle Scholar
  21. Su, Y. F., Harden, T. K. & Perkins, J. P. (1980). Catecholamine-specific desensitization of adenylate cyclase: evidence for a multistep process. J. biol. Chem., in press.Google Scholar
  22. Terasaki, W. L., Brooker, G., de Vellis, J., English, D., Hsu, C. Y. & Moylan, R. R. (1978). Involvement of cyclic AMP and protein synthesis in catecholamine refractoriness. Adv. cycl.Nucl.Res., 9, 33–52.Google Scholar
  23. Wessels, M. R., Mullikin, D. & Lefkowitz, R. J. (1978). Differences between agonist and antagonist binding following β-adrenergic receptor desensitization. J. biol. Chem., 253, 3371–3373.PubMedGoogle Scholar
  24. Wessels, M. R., Mullikin, D. & Lefkowitz, R. J. (1979). Selective alteration of high affinity agonist binding: A mechanism of β-adrenergic receptor desensitization. Mol. Pharmac., 16, 10–20.Google Scholar
  25. Williams, L. T. & Lefkowitz, R. J. (1977). Slowly reversible binding of a β-adrenergic agonist to a nucleotide sensitive state of the β-adrenergic receptor. J. biol. Chem., 252, 7207–7213.PubMedGoogle Scholar

Copyright information

© The contributors 1980

Authors and Affiliations

  • R. J. Lefkowitz
    • 1
  1. 1.Howard Hughes Medical Institute Laboratory, Departments of Medicine (Cardiovascular) and BiochemistryDuke University Medical CenterDurhamUSA

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