New insights into beta2-adrenoceptor signaling in the adult rat heart.
OBJECTIVE
The role of cAMP in beta(2)-adrenoceptor signaling and its functional relevance in adult rat heart has been the subject of considerable controversy. Therefore, we investigated the beta(2)-adrenoceptor pathways in both adult cardiomyocytes and in the intact hearts of Wistar rats with respect to protein kinase A (at Ser16)-, the key event in shortening of relaxation time, and CaM kinase II (at Thr17)-dependent phospholamban phosphorylation.


METHODS
Contractile and cellular beta(1)/beta(2)-adrenergic responses were studied in parallel on the same perfused rat heart. (-)Isoproterenol and the beta(2)-adrenergic agonists zinterol and procaterol were used to discriminate the beta-adrenoceptor subtype-related actions.


RESULTS
Beta(2)-adrenoceptor stimulation induces protein kinase A-dependent phospholamban phosphorylation in both adult cardiomyocytes and in adult hearts of rats. The beta(2)-adrenoceptor-mediated shortening of relaxation time in the heart correlates with Ser16 phosphorylation. Adenosine elicited antiadrenergic action on both beta(1)- and beta(2)-adrenergic signaling cascades by reducing the phosphorylation status of phospholamban. Only beta(1)-adrenoceptor stimulation produced significant CaM kinase II-related Thr17 phosphorylation, troponin I phosphorylation and activation of phosphorylase a.


CONCLUSIONS
Our findings clearly show that beta(2)-adrenoceptor signaling is coupled to phospholamban phosphorylation and shortening of relaxation time in the adult rat heart.
Bartel
Sabine
S
Max Delbrück Center for Molecular Medicine, Berlin, Germany. s.bartel@mdc-berlin.de
Krause
Ernst-Georg
EG
Wallukat
Gerd
G
Karczewski
Peter
P
D000241:Adenosine / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology; D006321:Heart / Q000502:physiology*; D008297:Male; D032342:Muscle Cells / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D010762:Phosphorylase a / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D019210:Troponin I / Q000378:metabolism; D000099211:Phospholamban
D000241:Adenosine; D000318:Adrenergic beta-Agonists; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000252:Calcium-Transporting ATPases; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004983:Ethanolamines; D010762:Phosphorylase a; D011943:Receptors, Adrenergic, beta; D019210:Troponin I; D000099211:Phospholamban; C002904:zinterol