Abstract
Heart failure is a problem of increasing importance in medicine. An important characteristic of heart failure is reduced agonist-stimulated adenylyl cyclase activity (receptor desensitization) due to both diminished receptor number (receptor down regulation) and impaired receptor function (receptor uncoupling). These changes in the ß-adrenergic receptor (ß-AR) system, may in part account for some of the abnormalities of contractile function in this disease. Myocardial contraction is closely regulated by Gprotein coupled ß-adrenergic receptors through the action of the second messenger cAMP. The ß-AR receptors themselves are regulated by a set of specific kinases, termed the Gprotein-coupled receptor kinases (GRKs). The study of this complex system in vivo has recently been advanced by the development of transgenic and gene targeted (“knockout”) mouse models. Combining transgenic technology with sophisticated physiological measurements of cardiac hemodynamics is an extremely powerful strategy to study the regulation of myocardial contractility in the normal and failing heart.
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References
Cohn JN. Plasma norepinephrine and mortality. Clin Cardiol 1995;18(Suppl):I-9–I-12.
Cohn JN, Levine B, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB. Plasma norepinepherine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311:819–823.
Francis GS, CCohn JN, Johnson G, Rector TS, Goldman S, Simon A. Plasma norepinephrine, plasma renin activity and congestive heart failure. Circulation 1993;87[suppl]:VI40–VI48.
Brodde OE. Beta-adrenoceptors in cardiac disease. Pharmac Ther 1993;60:405–430.
Bristow MR, Minobe WA, Raynolds 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.
Ungerer M, Parruti G, Bohm M, Puzicha M, DeBlasi A, Erdmann E, Lohse MJ. Expression of β-arrestins and β-adrenergic receptor kinases in the failing human heart. Circ Res 1994;74:206–213.
Feldman AM. Experimental issues in assessment of G-protein function in cardiac disease. Circulation 1991;84:1852–1861.
Bristow MR, Hershberger RE, Port JD, Gilbert EM, Sandoval A, Rasmussen R, Cates AE, Feldman AM. β-adrenergic pathways in nonfailing and failing human ventricular myocardium. Circulation 1990;82:(suppl I)I12–I25.
Bohm M. Alterations of β-adrenoreceptor-G-protein-regulated adenylyl cyclase in heart failure. Mol Cell Bloche 1995;147:147–160.
Ungerer M, Bohm M, Elce JS, Erdman E, Lohse MJ. Altered expression of β-adrenergic receptors in the failing human heart. Circulation 1993;87:454–463.
Ping P, Gelzer-Bell R, Roth DA, Kiel D, Insel PA, Hammond HK. Reduced β-adrenergic receptor activation decreases G-protein expression and β-adrenergic receptor kinase activity in porcine heart. J Clin Invest 1995;95:1271–1280.
Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson ED. Decreased catecholamine sensitivity and β-adrenergic-receptor density in failing human hearts. N Engl J Med 1982;307:205–211.
Milano CA, Allen LF, Rockman HA, Dolber PC, McMinn TR, Chien KR Johnson TD, Bond RA, Lefkowitz RJ. Enhanced myocardial function in transgenic mice overexpressing the β2-adrenergic receptor. Science 1994;264:582–586.
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.
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 βARK inhibitor. Science 1995;268:1350–1353.
Rockman HA, Choi DJ, 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.
Rockman HA, Hamilton R, Milano CA, Mao L, Jones LR, Lefkowitz RJ. Enhanced myocardial relaxation in vivo in transgenic mice overexpressing the β2-adrenergic receptor is associated with reduced phospholamban protein. J Clin Invest 1996;97:1618–1623.
Lefkowitz RJ, Cotecchia S, Samama P, Costa T. Constitutive activity of receptors coupled to guanine nucleotide regulatory proteins. Trends Pharmacol Sci 1993;14:303–307.
Schipani E, Langman CB, Parfitt AM, Jensen GS, Kikuchi S, Kooh SW, Cole WG, Juppner H. Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen’s metaphyseal chondrodysplasia. N Engl J Med 1996;335:708–714.
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.
Rockman HA, Ross RS, Harris AN, Knowlton KU, Steinhelper ME, Field L, Ross J Jr, Chien KR. Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy. Proc Natl Acad Sci USA 1991;88:8277–8281.
Rockman HA, Ono S, Ross RS, Jones LR, Karim M, Bhargava V, Ross J Jr, Chien KR. Molecular and physiological alterations in murine ventricular dysfunction. Proc Natl Acad Sci USA 1994;91:2694–2698.
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Rockman, H.A. (1997). Uncoupling of G-Protein Coupled Receptors in vivo: Insights from Transgenic Mice. In: Sideman, S., Beyar, R. (eds) Analytical and Quantitative Cardiology. Advances in Experimental Medicine and Biology, vol 430. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5959-7_6
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DOI: https://doi.org/10.1007/978-1-4615-5959-7_6
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