Real-time relationship between PKA biochemical signal network dynamics and increased action potential firing rate in heart pacemaker cells: Kinetics of PKA activation in heart pacemaker cells

cAMP-PKA protein kinase is a key nodal signaling pathway that regulates a wide range of heart pacemaker cell functions. These functions are predicted to be involved in regulation of spontaneous action potential (AP) generation of these cells. Here we investigate if the kinetics and stoichiometry of...

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Bibliographic Details
Published in:Journal of molecular and cellular cardiology Vol. 86; p. 168
Main Authors: Yaniv, Yael, Ganesan, Ambhighainath, Yang, Dongmei, Ziman, Bruce D, Lyashkov, Alexey E, Levchenko, Andre, Zhang, Jin, Lakatta, Edward G
Format: Journal Article
Language:English
Published: England 01.09.2015
Subjects:
Action Potentials - drug effects
Animals
Calcium Signaling
Cyclic AMP-Dependent Protein Kinases - genetics
Cyclic AMP-Dependent Protein Kinases - metabolism
Humans
Kinetics
Phosphodiesterase Inhibitors - administration & dosage
Phosphorylation - drug effects
Rabbits
Receptors, Adrenergic, beta - metabolism
Sarcoplasmic Reticulum - drug effects
Sarcoplasmic Reticulum - metabolism
Sarcoplasmic Reticulum - pathology
Signal Transduction - drug effects
Sinoatrial Node - drug effects
Sinoatrial Node - metabolism
Sinoatrial Node - pathology
Phosphorylation
Computational modeling
Pacemaker
Coupled-clock system
ISSN:1095-8584, 1095-8584
Online Access:Get full text
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Summary:cAMP-PKA protein kinase is a key nodal signaling pathway that regulates a wide range of heart pacemaker cell functions. These functions are predicted to be involved in regulation of spontaneous action potential (AP) generation of these cells. Here we investigate if the kinetics and stoichiometry of increase in PKA activity match the increase in AP firing rate in response to β-adrenergic receptor (β-AR) stimulation or phosphodiesterase (PDE) inhibition, that alters the AP firing rate of heart sinoatrial pacemaker cells. In cultured adult rabbit pacemaker cells infected with an adenovirus expressing the FRET sensor AKAR3, the EC50 in response to graded increases in the intensity of β-AR stimulation (by Isoproterenol) the magnitude of the increases in PKA activity and the spontaneous AP firing rate were similar (0.4±0.1nM vs. 0.6±0.15nM, respectively). Moreover, the kinetics (t1/2) of the increases in PKA activity and spontaneous AP firing rate in response to β-AR stimulation or PDE inhibition were tightly linked. We characterized the system rate-limiting biochemical reactions by integrating these experimentally derived data into a mechanistic-computational model. Model simulations predicted that phospholamban phosphorylation is a potent target of the increase in PKA activity that links to increase in spontaneous AP firing rate. In summary, the kinetics and stoichiometry of increases in PKA activity in response to a physiological (β-AR stimulation) or pharmacological (PDE inhibitor) stimuli match those of changes in the AP firing rate. Thus Ca(2+)-cAMP/PKA-dependent phosphorylation limits the rate and magnitude of increase in spontaneous AP firing rate.
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ISSN:1095-8584
1095-8584
DOI:10.1016/j.yjmcc.2015.07.024