G(i) protein-mediated functional compartmentalization of cardiac β2- adrenergic signaling

Meike Kuschel, Ying Ying Zhou, Heping Cheng, Sheng Jun Zhang, Ye Chen-Izu, Edward G. Lakatta, Rui Ping Xiao

Research output: Contribution to journalArticle

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Abstract

In contrast to β1-adrenoreceptor (β1-AR) signaling, β2-AR stimulation in cardiomyocytes augments L-type Ca2+ current in a cAMP- dependent protein kinase (PKA)dependent manner but fails to phosphorylate phospholamban, indicating that the β2-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 β2-AR stimulation, converting the localized β2-AR signaling to a global signaling mode similar to that of 131-AR. Thus, β2-AR-mediated G(i) activation constricts the cAMP signaling to the sarcolemma. PTX treatment did not significantly affect the β2-AR-stimulated PKA activation. Similar to G(i) inhibition, a protein phosphatase inhibitor, calyculin A (3 x 10-8 M), selectively enhanced the β2-AR but not β1-AR- mediated contractile response. Furthermore, PTX and calyculin A treatment had a non-additive potentiating effect on the β2-AR-mediated positive inotropic response. These results suggest that the interaction of the β2-AR-coupled G(i) and G(s) signaling affects the local balance of protein kinase and phosphatase activities. Thus, the additional coupling of β2-AR to G(i) proteins is a key factor causing the compartmentalization of β2-AR-induced cAMP signaling.

Original languageEnglish (US)
Pages (from-to)22048-22052
Number of pages5
JournalJournal of Biological Chemistry
Volume274
Issue number31
DOIs
StatePublished - Jul 30 1999
Externally publishedYes

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Pertussis Toxin
Adrenergic Agents
Protein Kinases
Phosphoprotein Phosphatases
Sarcolemma
Proteins
Cyclic AMP-Dependent Protein Kinases
Cardiac Myocytes
Phosphorylation
Chemical activation
phospholamban
calyculin A

ASJC Scopus subject areas

  • Biochemistry

Cite this

G(i) protein-mediated functional compartmentalization of cardiac β2- adrenergic signaling. / Kuschel, Meike; Zhou, Ying Ying; Cheng, Heping; Zhang, Sheng Jun; Chen-Izu, Ye; Lakatta, Edward G.; Xiao, Rui Ping.

In: Journal of Biological Chemistry, Vol. 274, No. 31, 30.07.1999, p. 22048-22052.

Research output: Contribution to journalArticle

Kuschel, Meike ; Zhou, Ying Ying ; Cheng, Heping ; Zhang, Sheng Jun ; Chen-Izu, Ye ; Lakatta, Edward G. ; Xiao, Rui Ping. / G(i) protein-mediated functional compartmentalization of cardiac β2- adrenergic signaling. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 31. pp. 22048-22052.
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