CARDIAC-SPECIFIC OVEREXPRESSION OF ALPHA(1B)AR REGULATES BETA-AR ACTIVITY VIA MOLECULAR CROSSTALK

alpha(1)AR play an important role in regulating cardiac contractility under many physiological and pathological conditions. We are thus inte rested in determining the molecular events coupled to alpha(1)AR signa lling pathways in the heart and in the possibility of molecular crosst alk between different receptor systems, We have analysed transgenic mo use lines which overexpress the wild-type (WT) alpha(1B)AR (3.0 +/- 0. 26 pmol/mg, TgA and 2.1 +/- 0.26 pmol/mg, TgB) compared to non-transge nic animals (0.02 +/- 0.002 pmol/mg). Ligand binding studies showed th at overexpression of alpha(1B)AR did not affect the beta AR density or their affinity for a specific antagonist. Basal adenylyl cyclase acti vity, but not basal cAMP levels, was increased in the transgenic anima ls, while isoproterenol-mediated fold stimulation of adenylyl cyclase activity of both transgenic mouse lines was decreased significantly. I n addition, high-affinity beta AR agonist binding was severely impaire d in the transgenic animals. We found increases in the amount of two C a2+-independent (delta and epsilon) and one Ca2+-dependent (beta II) p rotein kinase C (PKC) isoforms associated with the particulate fractio n, suggesting that PKC may be involved in the heterologous desensitiza tion of PAR by alpha(1B)AR. These results indicate that following alph a(1B)AR overexpression, the PAR system may be uncoupled via molecular crosstalk. (C) 1998 Academic Press