Dynamic protein kinase a activities induced by β-adrenoceptors dictate signaling propagation for substrate phosphorylation and myocyte contraction

Dagoberto Soto, Vania De Arcangelis, Jin Zhang, Yang Kevin Xiang

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

CAMP/protein kinase (PK)A activation represents a key signaling mechanism for neurohormonal stimulation of diversified physiological processes. Using real-time, fluorescence resonance energy transfer-based imaging of PKA activity in neonatal cardiac myocytes, we report that sustained activation of PKA induced by β-adrenoceptor (βAR) dictates signaling propagation for substrate phosphorylation and myocyte contraction. Activation of βARs in wild-type myocytes induces strong and sustained PKA activities, which are rapidly attenuated on washing away agonist or adding antagonist to the cells. The sustained PKA activities promote signaling propagation to the sarcoplasmic reticulum for phosphorylation of phospholamban and increases in myocyte contraction. Addition of antagonist after βAR stimulation significantly attenuates PKA phosphorylation of phospholamban and rapidly reduces contraction rate increases. Moreover, stimulation of β1AR subtype induces PKA activities similar to those in wild-type cells. In contrast, stimulation of β2AR subtype induces strong initial activation of PKA similar to those induced by β1AR; however, the activities are rapidly decreased to baseline levels. The transient PKA activities are sufficient for phosphorylation of the overexpressed β2ARs under agonist stimulation, but not phospholamban. Further analysis reveals that phosphodiesterase 4 is the major family that shapes PKA activities under βAR stimulation. Inhibition of phosphodiesterase 4 extends β2AR-induced PKA activities, promotes PKA phosphorylation of phospholamban, and ultimately enhances myocyte contraction responses. Together, our data have revealed insights into kinetics of PKA activities in signaling propagation under neurohormonal stimulation.

Original languageEnglish (US)
Pages (from-to)770-779
Number of pages10
JournalCirculation Research
Volume104
Issue number6
DOIs
StatePublished - Mar 27 2009
Externally publishedYes

Fingerprint

Adrenergic Receptors
Protein Kinases
Muscle Cells
Phosphorylation
Type 4 Cyclic Nucleotide Phosphodiesterase
Physiological Phenomena
Fluorescence Resonance Energy Transfer
Sarcoplasmic Reticulum
Cyclic AMP-Dependent Protein Kinases
Cardiac Myocytes
phospholamban

Keywords

  • Adrenergic receptor
  • Contraction
  • Phospholamban
  • Protein kinase A phosphorylation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Dynamic protein kinase a activities induced by β-adrenoceptors dictate signaling propagation for substrate phosphorylation and myocyte contraction. / Soto, Dagoberto; De Arcangelis, Vania; Zhang, Jin; Xiang, Yang Kevin.

In: Circulation Research, Vol. 104, No. 6, 27.03.2009, p. 770-779.

Research output: Contribution to journalArticle

@article{f716757a1fbf46b2af66028cca07f75e,
title = "Dynamic protein kinase a activities induced by β-adrenoceptors dictate signaling propagation for substrate phosphorylation and myocyte contraction",
abstract = "CAMP/protein kinase (PK)A activation represents a key signaling mechanism for neurohormonal stimulation of diversified physiological processes. Using real-time, fluorescence resonance energy transfer-based imaging of PKA activity in neonatal cardiac myocytes, we report that sustained activation of PKA induced by β-adrenoceptor (βAR) dictates signaling propagation for substrate phosphorylation and myocyte contraction. Activation of βARs in wild-type myocytes induces strong and sustained PKA activities, which are rapidly attenuated on washing away agonist or adding antagonist to the cells. The sustained PKA activities promote signaling propagation to the sarcoplasmic reticulum for phosphorylation of phospholamban and increases in myocyte contraction. Addition of antagonist after βAR stimulation significantly attenuates PKA phosphorylation of phospholamban and rapidly reduces contraction rate increases. Moreover, stimulation of β1AR subtype induces PKA activities similar to those in wild-type cells. In contrast, stimulation of β2AR subtype induces strong initial activation of PKA similar to those induced by β1AR; however, the activities are rapidly decreased to baseline levels. The transient PKA activities are sufficient for phosphorylation of the overexpressed β2ARs under agonist stimulation, but not phospholamban. Further analysis reveals that phosphodiesterase 4 is the major family that shapes PKA activities under βAR stimulation. Inhibition of phosphodiesterase 4 extends β2AR-induced PKA activities, promotes PKA phosphorylation of phospholamban, and ultimately enhances myocyte contraction responses. Together, our data have revealed insights into kinetics of PKA activities in signaling propagation under neurohormonal stimulation.",
keywords = "Adrenergic receptor, Contraction, Phospholamban, Protein kinase A phosphorylation",
author = "Dagoberto Soto and {De Arcangelis}, Vania and Jin Zhang and Xiang, {Yang Kevin}",
year = "2009",
month = "3",
day = "27",
doi = "10.1161/CIRCRESAHA.108.187880",
language = "English (US)",
volume = "104",
pages = "770--779",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "6",

}

TY - JOUR

T1 - Dynamic protein kinase a activities induced by β-adrenoceptors dictate signaling propagation for substrate phosphorylation and myocyte contraction

AU - Soto, Dagoberto

AU - De Arcangelis, Vania

AU - Zhang, Jin

AU - Xiang, Yang Kevin

PY - 2009/3/27

Y1 - 2009/3/27

N2 - CAMP/protein kinase (PK)A activation represents a key signaling mechanism for neurohormonal stimulation of diversified physiological processes. Using real-time, fluorescence resonance energy transfer-based imaging of PKA activity in neonatal cardiac myocytes, we report that sustained activation of PKA induced by β-adrenoceptor (βAR) dictates signaling propagation for substrate phosphorylation and myocyte contraction. Activation of βARs in wild-type myocytes induces strong and sustained PKA activities, which are rapidly attenuated on washing away agonist or adding antagonist to the cells. The sustained PKA activities promote signaling propagation to the sarcoplasmic reticulum for phosphorylation of phospholamban and increases in myocyte contraction. Addition of antagonist after βAR stimulation significantly attenuates PKA phosphorylation of phospholamban and rapidly reduces contraction rate increases. Moreover, stimulation of β1AR subtype induces PKA activities similar to those in wild-type cells. In contrast, stimulation of β2AR subtype induces strong initial activation of PKA similar to those induced by β1AR; however, the activities are rapidly decreased to baseline levels. The transient PKA activities are sufficient for phosphorylation of the overexpressed β2ARs under agonist stimulation, but not phospholamban. Further analysis reveals that phosphodiesterase 4 is the major family that shapes PKA activities under βAR stimulation. Inhibition of phosphodiesterase 4 extends β2AR-induced PKA activities, promotes PKA phosphorylation of phospholamban, and ultimately enhances myocyte contraction responses. Together, our data have revealed insights into kinetics of PKA activities in signaling propagation under neurohormonal stimulation.

AB - CAMP/protein kinase (PK)A activation represents a key signaling mechanism for neurohormonal stimulation of diversified physiological processes. Using real-time, fluorescence resonance energy transfer-based imaging of PKA activity in neonatal cardiac myocytes, we report that sustained activation of PKA induced by β-adrenoceptor (βAR) dictates signaling propagation for substrate phosphorylation and myocyte contraction. Activation of βARs in wild-type myocytes induces strong and sustained PKA activities, which are rapidly attenuated on washing away agonist or adding antagonist to the cells. The sustained PKA activities promote signaling propagation to the sarcoplasmic reticulum for phosphorylation of phospholamban and increases in myocyte contraction. Addition of antagonist after βAR stimulation significantly attenuates PKA phosphorylation of phospholamban and rapidly reduces contraction rate increases. Moreover, stimulation of β1AR subtype induces PKA activities similar to those in wild-type cells. In contrast, stimulation of β2AR subtype induces strong initial activation of PKA similar to those induced by β1AR; however, the activities are rapidly decreased to baseline levels. The transient PKA activities are sufficient for phosphorylation of the overexpressed β2ARs under agonist stimulation, but not phospholamban. Further analysis reveals that phosphodiesterase 4 is the major family that shapes PKA activities under βAR stimulation. Inhibition of phosphodiesterase 4 extends β2AR-induced PKA activities, promotes PKA phosphorylation of phospholamban, and ultimately enhances myocyte contraction responses. Together, our data have revealed insights into kinetics of PKA activities in signaling propagation under neurohormonal stimulation.

KW - Adrenergic receptor

KW - Contraction

KW - Phospholamban

KW - Protein kinase A phosphorylation

UR - http://www.scopus.com/inward/record.url?scp=64249083698&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=64249083698&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.108.187880

DO - 10.1161/CIRCRESAHA.108.187880

M3 - Article

C2 - 19213958

AN - SCOPUS:64249083698

VL - 104

SP - 770

EP - 779

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 6

ER -