G(i) protein-mediated functional compartmentalization of cardiac beta(2)-adrenergic signaling.
In contrast to beta(1)-adrenoreceptor (beta(1)-AR) signaling, beta(2)-AR stimulation in cardiomyocytes augments L-type Ca(2+) current in a cAMP-dependent protein kinase (PKA)-dependent manner but fails to phosphorylate phospholamban, indicating that the beta(2)-AR-induced cAMP/PKA signaling is highly localized. Here we show that inhibition of G(i) proteins with pertussis toxin (PTX) permits a full phospholamban phosphorylation and a de novo relaxant effect following beta(2)-AR stimulation, converting the localized beta(2)-AR signaling to a global signaling mode similar to that of beta(1)-AR. Thus, beta(2)-AR-mediated G(i) activation constricts the cAMP signaling to the sarcolemma. PTX treatment did not significantly affect the beta(2)-AR-stimulated PKA activation. Similar to G(i) inhibition, a protein phosphatase inhibitor, calyculin A (3 x 10(-8) M), selectively enhanced the beta(2)-AR but not beta(1)-AR-mediated contractile response. Furthermore, PTX and calyculin A treatment had a non-additive potentiating effect on the beta(2)-AR-mediated positive inotropic response. These results suggest that the interaction of the beta(2)-AR-coupled G(i) and G(s) signaling affects the local balance of protein kinase and phosphatase activities. Thus, the additional coupling of beta(2)-AR to G(i) proteins is a key factor causing the compartmentalization of beta(2)-AR-induced cAMP signaling.
Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, National Institutes of Health, Baltimore, Maryland 21224, USA.
M
M
Kuschel
Y Y
YY
Zhou
H
H
Cheng
S J
SJ
Zhang
Y
Y
Chen
E G
EG
Lakatta
R P
RP
Xiao
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins / Q000378:metabolism; D048429:Cell Size; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D008387:Marine Toxins; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000166:cytology*; D010080:Oxazoles / Q000494:pharmacology; D037342:Pertussis Toxin; D010766:Phosphorylation; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D000099211:Phospholamban
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004983:Ethanolamines; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D008387:Marine Toxins; D010080:Oxazoles; D037342:Pertussis Toxin; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D013873:Thionucleotides; D014662:Vasoconstrictor Agents; D010566:Virulence Factors, Bordetella; D000099211:Phospholamban; C016957:adenosine-3',5'-cyclic phosphorothioate; C026777:ICI 118551; C002904:zinterol; C059041:calyculin A