Altering Adrenergic Signaling and Cardiac Function in Transgenic Mice

  • Walter J. Koch
  • Robert J. Lefkowitz
Part of the Contemporary Endocrinology book series (COE, volume 6)


The ability to maintain and manipulate mouse embryos in vitro, perfected over the last decade, has launched the expanding field of transgenic experimentation models. With the successful insertion of foreign genes into the mouse genome, important in vivo transgenic models have emerged in several venues of biomedical research, which allows for a broader understanding of pathological conditions. Transgenic mice permit investigation of the consequences of a protein’s overexpression in specific tissues. In addition, the loss of function of a protein or enzyme in a given organ can be examined by overexpression of an inhibitor peptide or a dominant-negative mutant. Elimination of a protein from all tissues can also be achieved by gene disruption techniques. These approaches are well suited to study the physiological roles of cellular proteins.


Adenylyl Cyclase Adrenergic Receptor Inverse Agonist Adrenergic Signaling Transgenic Manipulation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Field LJ. Transgenic mice in cardiovascular research. Annu Rev Physiol 1993;55:97–114PubMedCrossRefGoogle Scholar
  2. 2.
    Koch WJ, Milano CA, Lefkowitz RJ. Transgenic Manipulation of myocardial G-protein-coupled receptors and receptor kinases. Circ Res 1996;78:511–516.PubMedCrossRefGoogle Scholar
  3. 3.
    Cohn JN. Plasma norepinephrine and mortality. Clin Cardiol 1995;18(Suppl):I9–12.PubMedCrossRefGoogle Scholar
  4. 4.
    Brodde O. Beta-adrenoceptors in cardiac disease. Pharmac of Ther 1993;60:405–430.CrossRefGoogle Scholar
  5. 5.
    Xiao R-P, Lakatta EG. β1adrenoceptor stimulation and β2-adrenoceptor stimulation differ in their effects on contraction, cytosolic Ca2+, and Ca2+ current in single rat Ventricular cells. Cir Res 1993;73:286–300.CrossRefGoogle Scholar
  6. 6.
    Atschuld RA, Starling RC, Hamlin RL, Billman GE, Hensley J, Castillo L, Fertel RH, Hohl CM, Robitaille P-ML, Jones LR, Xiao R-P, Lakatta EG. Response of failing canine and human heart cells to β2-adrenergic stimulation. Circulation 1995;92:1612–1618.CrossRefGoogle Scholar
  7. 7.
    Bristow MR, Minobe W, Rasmussen R, Hersberger RE, Hoffman BB. Alpha-1 adrenergic receptors in the nonfailing and failing human heart. J Pharmacol Exp Ther 1988;247:1039–1045.PubMedGoogle Scholar
  8. 8.
    Terzic A, Puceat M, Vassort G, Vogel SM. Cardiac α1adrenoceptors: An overview. Pharmacol Rev 1993;45:147–175.PubMedGoogle Scholar
  9. 9.
    Kariya K, Karns LR, Simpson PC. expression of a constitutively activated mutant of the β-isozyme of protein kinase C in cardiac myocytes stimulated the promoter of the β-myosin heavy chain isogene. J Biol Chem 1991;266:10023–10026.PubMedGoogle Scholar
  10. 10.
    Hausdorff WP, Caron MG, Lefkowitz RJ. Turning off the signal: Desensitization of β-Adrenergic receptor function. FASEB 1990;4:2881–2889.Google Scholar
  11. 11.
    Inglese J, Freedman NJ, Koch WJ, Lefkowitz RJ. Structure and mechanism of the G-protein-coupled receptor kinases. J Biol Chem 1993;268:23735–23738.PubMedGoogle Scholar
  12. 12.
    Freedman NJ, Liggett SB, Drachman DE, Pie G, Caron MG, Lefkowitz RJ. Phosphorylation and desensitization of the human β1-adrenergic receptor: Involvement of G-protein-coupled receptor kinases and cAMP-dependent protein kinase. J Biol Chem 1995;270:17953–17961.PubMedCrossRefGoogle Scholar
  13. 13.
    Koch WJ, Rockman HA, Samama P, Hamilton R, Bond RA, Milano CA, Lefkowitz RJ. Reciprocally altered cardiac function in transgenic mice overexpressing the β-adrenergic receptor kinase or a βARKl inhibitor. Science 1995;268:1350–1353.PubMedCrossRefGoogle Scholar
  14. 14.
    Rockman HA, Choi D-J, Rahman NU, Akhter SA, Lefkowitz RJ, Koch WJ. Receptor specific in vivo desensitization by the G-protein-coupled receptor kinase-5 in transgenic mice. Proc Natl Acad Sci USA 1996;93:9954–9959.PubMedCrossRefGoogle Scholar
  15. 15.
    Pitcher JA, Inglese J, Higgins JB, Arriza JL, Casey PJ, Kim C, Benovic JL, Kwatra MM, Caron MG, Lefkowitz RJ. Role of βγ-subunits of G proteins in targeting the β-adrenergic receptor kinase to membrane-bound receptors. Science 1993;257:1264–1267.CrossRefGoogle Scholar
  16. 16.
    Koch WJ, Inglese J, Stone WC, Lefkowitz RJ. The binding site for the βγ-subunits of heterotrimeric G proteins on the β-adrenergic receptor kinase. J Biol Chem 1993;268:8256–8260.PubMedGoogle Scholar
  17. 17.
    Premont RT, Koch WJ, Inglese J, Lefkowitz RJ. Identification, purification and characterization of GRK5, a member of the family of G-protein-receptor kinases. J Biol Chem 1994;269:6832–6841.PubMedGoogle Scholar
  18. 18.
    Pitcher JA, Fredericks ZL, Stone WC, Premont RT, Stoffel RH, Koch WJ, Lefkowitz RJ. Phosphatidylinositol-4,5-bisphosphate (PIP2)-enhanced G-protein-coupled receptor kinase (GRK) activity: Location, structure, and regulation of the PIP2 binding site distinguishes the GRK subfamilies. J Biol Chem 1996;271:24907–24913.PubMedCrossRefGoogle Scholar
  19. 19.
    Pitcher JA, Touhara K, Payne ES, Lefkowitz RJ. Pleckstrin homology domain-dedicated membrane association and activation of the beta-adrenergic receptor kinase requires coordinate interaction with Gβγ subunits and lipids. J Biol Chem 1995;270:11709–11710.Google Scholar
  20. 20.
    Bristow MR, Minobe WA, Reynolds MV, Port JD, Rasmussen R, Ray PE, Feldman AM. Reduced β1 receptor messenger RNA abundance in the failing human heart. J Clin Invest 1993;92:2737–2745.PubMedCrossRefGoogle Scholar
  21. 21.
    Lohse MJ. G-protein-coupled receptor kinases and the heart. Trends Cardiovasc Med 1995;5:63–68.PubMedCrossRefGoogle Scholar
  22. 22.
    Feldman AM. Experimental issues in assessment of G protein function in cardiac disease. Circulation 1991;84:1852–1861.PubMedCrossRefGoogle Scholar
  23. 23.
    Böhm M. Alteration of β-adrenoreceptor-G-protein-regulated adenylyl cyclase in heart failure. Mol Cell Biochem 1995;147:147–160.PubMedCrossRefGoogle Scholar
  24. 24.
    Milano CA, Allen LF, Rockman HA, Dolber PC, McMinn TR, Chien KR, Johnson TD, Bond RA, Lefkowitz RJ. Enhanced myocardial function in transgenic mice overexpression the β2-adrenergic receptor. Science 1994;264:582–586.PubMedCrossRefGoogle Scholar
  25. 25.
    Bond RA, Johnson TD, Milano CA, Rockman HA, McMinn TR Apparsunndaram S, Kenakin TP, Allen LF, Lefkowitz RJ. Physiologic effects of inverse agonists in transgenic mice with myocardial overexpression of the β2-adrenoceptor. Nature 1995;374:272–275.PubMedCrossRefGoogle Scholar
  26. 26.
    Rockman HA, Hamilton R, Milano CA, Mao L, Jones LR, Lefkowitz RJ. Enhanced myocardial relaxation in vivo in transgenic mice overexpression the β2-adrenergic receptor is associated with reduced phospholamban protein. J Clin Invest 1996;97:1–6.CrossRefGoogle Scholar
  27. 27.
    Lefkowitz RJ, Cotecchia S, Samama P, Costa T. Constitutive activity of receptors coupled to guanine nucleotide proteins. Trends Pharmacol Sci 1993;14:303–307.PubMedCrossRefGoogle Scholar
  28. 28.
    Milano CA, Dolber PC, Rockman HA, Bond RA, Venable ME, Allen LF, Lefkowitz RJ. Myocardial expression of a constitutively active α1B-adrenergic receptor in transgenic mice induces cardiac hypertrophy. Proc Natl Acad Sci USA, 1994;91:10109–10113.PubMedCrossRefGoogle Scholar
  29. 29.
    Bristow MR, O’Connel JB, Gilbert EM, French WJ, Leatherman G, Kantrowitz NE, Orie J, Smucker ML, Marshall G, Kelly P, Deitchman D, Anderson JL. Dose-response of chronic β-blocker treatment in heart failure from either idiopathic dilated or ischemie cardiomyopathy. Bucindolol Investigators. Circulation 1994;89:1632–1642.Google Scholar
  30. 30.
    Ping P, Gelzer-Bell R, Roth DA, Kiel D, Insel PA, Hammond HK. Reduced β-adrenergic receptor activation decrease G protein expression and β-adrenergic receptor kinase activity in porcine heart. J Clin Invest 1995;95:1271–1280.PubMedCrossRefGoogle Scholar
  31. 31.
    Gaudin C, Ishikawa Y, Wight DC, Mahdavi V, Nadal-Ginard B, Wagner TE, Vatner DE, Homey CJ. Overexpression of Gsa protein in the hearts of transgenic mice. J Clin Invest 1995;95:1676–1683.PubMedCrossRefGoogle Scholar
  32. 32.
    Iwase M, Bishop SP, Uechi M, Vatner DE, Shannon RP, Kudej RK, Wight DC, Wagner TE, Ishikawa Y, Homey CJ, Vatner SF. Adverse effects of chronic endogenous sympathetic drive induced by cardiac Gsa overexpression. Circ Res 1996;78:517–524.PubMedCrossRefGoogle Scholar
  33. 33.
    Rockman HA, Koch WJ, Milano CA, Lefkowitz RJ. Myocardial β-adrenergic receptor signaling in vivo: Insights from transgenic mice. J Mol Med 1996;74:489–495.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Walter J. Koch
  • Robert J. Lefkowitz

There are no affiliations available

Personalised recommendations