Coupling function of endogenous alpha(1)- and beta-adrenergic receptors inmouse cardiomyocytes

Genetically altered mouse models constitute unique systems to delineate the role of adrenergic receptor (AR) signaling mechanisms as modulators of car diomyocyte function. The interpretation of results from these models depend s on knowledge of the signaling properties of endogenous ARs in mouse cardi omyocytes. In the present study, we identify for the first time several def ects in AR signaling in cardiomyocytes cultured from mouse ventricles. beta (1)-ARs induce robust increases in cAMP accumulation and the amplitude of t he calcium and cell motion transients in mouse cardiomyocytes. Selective be ta(2)-AR stimulation increases the amplitude of calcium and motion transien ts, with only a trivial rise in cAMP accumulation in comparison. beta(2)-AR responses are not influenced by pertussis toxin in cultured mouse cardiomy ocytes. alpha(1)-ARs fail to activate phospholipase C, the extracellular si gnal-regulated protein kinase, p38-MAPK, or stimulate hypertrophy in mouse cardiomyocytes. Control experiments establish that this is not due to a les ion in distal elements in the signaling machinery, because these responses are induced by protease-activated receptor-1 agonists and phospholipase C i s activated by Pasteurella multocida toxin (a G(q) alpha-subunit agonist), Surprisingly, norepinephrine activates p38-MAPK via beta-ARs in mouse cardi omyocytes, but beta-AR activation of p38-MAPK alone is not sufficient to in duce cardiomyocyte hypertrophy. Collectively, these results identify a gene ralized defect in alpha(1)-AR signaling and a defect in beta(2)-AR linkage to cAMP (although not to an inotropic response) in cultured mouse cardiomyo cytes, These naturally occurring vagaries in AR signaling in mouse cardiomy ocytes provide informative insights into the requirements for hypertrophic signaling and impact on the value of mouse cardiomyocytes as a reconstituti on system to investigate AR signaling in the heart.