The angiotensin II subtype 2 (AT2) receptor is linked to protein kinase C but not cAMP-dependent pathways in the cardiomyocyte.
To define the signal transduction pathway linked to the cardiac angiotensin II (AII) receptor type 2 (AT2-R), cardiomyocytes were prepared as primary culture from 7-day-old chick embryo hearts. Protein kinase C (PKC) activity was assayed in membrane and cytosolic fractions of the cardiac cells. AII significantly (p < 0.05) increased membrane PKC activity and decreased cytosolic PKC activity, in a concentration-dependent manner, suggesting a translocation of PKC from cytosol to membrane. AT2-R blockade by its antagonist, PD123319, produced a dose-dependent antagonism of AII-induced activation of PKC. PD123319, at 10(-6) M or greater concentrations, completely antagonized AII-induced PKC activation, in contrast to a small reduction in PKC activity by the AII receptor type 1 (AT1-R) antagonist losartan. Isoproterenol-induced cAMP generation was significantly (p < 0.05) blunted by AII. AT2-R blockade did not alter AII-induced reduction of beta-adrenoceptor-mediated increases in cAMP generation, in contrast with AT1-R blockade, which abolished AII-induced reduction of beta-adrenergic-mediated cAMP production. These data suggest that AT2 receptors have a previously unrecognized, role in the heart, namely, coupling AII to PKC.
Rabkin
S W
SW
Department of Medicine (Cardiology), University of British Columbia, Vancouver, Canada.
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002642:Chick Embryo; D000242:Cyclic AMP / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D019808:Losartan; D009206:Myocardium / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D011943:Receptors, Adrenergic, beta; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C073402:PD 123319; D000242:Cyclic AMP; D011493:Protein Kinase C; D019808:Losartan; D007545:Isoproterenol