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Vol. 58, Issue 5, 887-894, November 2000
2- but Not
1-Adrenoceptors Expressed in Cardiac Myocytes from
12 Double Knockout Mice
Laboratory of Cardiovascular Science, Gerontology Research Center,
National Institute on Aging, National Institutes of Health, Baltimore,
Maryland (Y.-Y.Z., D.Y, W.-Z.Z., S.-J.Z, D.-J.W., E.G.L., H.C.,
R.-P.X.); National Laboratory of Biomembrane and Membrane
Biotechnology, Peking University, Beijing, People's Republic of China
(D.Y., H.C.); and Howard Hughes Medical Institute, Stanford University
Medical Center, Stanford, California (D.K.R., E.D., B.K.K.)
Although ligand-free, constitutive 
2-adrenergic receptor
(AR) signaling has been demonstrated in naive cell lines and in transgenic mice overexpressing cardiac 2-AR, it is
unclear whether the dominant cardiac -AR subtype,
1-AR, shares the ability of spontaneous activation. In
the present study, we expressed human 1- or
2-AR via recombinant adenoviral infection in ventricular myocytes isolated from 12-AR double
knockout mice, creating pure 1-AR and
2-AR systems with variable receptor densities. A
contractile response to a nonselective -AR agonist, isoproterenol, was absent in double knockout mouse myocytes but was fully restored after adenoviral 1-AR or adenoviral 2-AR
infection. Increasing the titer of adenoviral vectors (multiplicity of
infection 10-1000) led to a dose-dependent expression of
1- or 2-AR with a maximal density of
1207 ± 173 (36-fold over the wild-type control value) and
821 ± 38 fmol/mg protein (69-fold), respectively. Using confocal immunohistochemistry, we directly visualized the cellular distribution of 1-AR and 2-AR and found that both
subtypes were distributed on the cell surface membrane and transverse
tubules, resulting in a striated pattern. In the absence of ligand,
2-AR expression resulted in graded increases in baseline
cAMP and contractility up to 428% and 233% of control, respectively,
at the maximal 2-AR density. These effects were
specifically reversed by a 2-AR inverse agonist, ICI
118,551 (10
7 M). In contrast, overexpression of
1-AR, even at a greater density, failed to enhance
either basal cAMP or contractility; the alleged 1-AR
inverse agonist, CGP 20712A (106 M), had no significant
effect on basal contraction in these cells. Thus, we conclude that
acute 2-AR overexpression in cardiac myocytes elicits
significant physiological responses due to spontaneous receptor
activation; however, this property is -AR subtype specific because
1-AR does not exhibit agonist-independent spontaneous activation.
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