Cardiac-specific Overexpression ofα1BAR RegulatesβAR Activity Via Molecular Crosstalk

α1AR play an important role in regulating cardiac contractility under many physiological and pathological conditions. We are thus interested in determining the molecular events coupled toα1AR signalling pathways in the heart and in the possibility of molecular crosstalk between different receptor systems. We have analysed transgenic mouse lines which overexpress the wild-type (WT)α1BAR (3.0±0.26 pmol/mg, TgA and 2.1±0.26 pmol/mg, TgB) compared to non-transgenic animals (0.02±0.002 pmol/mg). Ligand binding studies showed that overexpression ofα1BAR did not affect theβAR density or their affinity for a specific antagonist. Basal adenylyl cyclase activity, but not basal cAMP levels, was increased in the transgenic animals, while isoproterenol-mediated fold stimulation of adenylyl cyclase activity of both transgenic mouse lines was decreased significantly. In addition, high-affinityβAR agonist binding was severely impaired in the transgenic animals. We found increases in the amount of two Ca2+-independent (δandc) and one Ca2+-dependent (βII) protein kinase C (PKC) isoforms associated with the particulate fraction, suggesting that PKC may be involved in the heterologous desensitization ofβAR byα1BAR. These results indicate that followingα1BAR overexpression, theβAR system may be uncoupled via molecular crosstalk.