A Compartmentalized Mathematical Model of the β1-Adrenergic Signaling System in Mouse Ventricular Myocytes

Abstract

The β1-adrenergic signaling system plays an important role in the functioning of cardiac cells. Experimental data shows that the activation of this system produces inotropy, lusitropy, and chronotropy in the heart, such as increased magnitude and relaxation rates of [Ca2+]i transients and contraction force, and increased heart rhythm. However, excessive stimulation of β1-adrenergic receptors leads to heart dysfunction and heart failure. In this paper, a comprehensive, experimentally based mathematical model of the β1-adrenergic signaling system for mouse ventricular myocytes is developed, which includes major subcellular functional compartments (caveolae, extracaveolae, and cytosol). The model describes biochemical reactions that occur during stimulation of β1-adrenoceptors, changes in ionic currents, and modifications of Ca2+ handling system. Simulations describe the dynamics of major signaling molecules, such as cyclic AMP and protein kinase A, in different subcellular compartments; the effects of inhibition of phosphodiesterases on cAMP production; kinetics and magnitudes of phosphorylation of ion channels, transporters, and Ca2+ handling proteins; modifications of action potential shape and duration; magnitudes and relaxation rates of [Ca2+]i transients; changes in intracellular and transmembrane Ca2+ fluxes; and [Na+]i fluxes and dynamics. The model elucidates complex interactions of ionic currents upon activation of β1-adrenoceptors at different stimulation frequencies, which ultimately lead to a relatively modest increase in action potential duration and significant increase in [Ca2+]i transients. In particular, the model includes two subpopulations of the L-type Ca2+ channels, in caveolae and extracaveolae compartments, and their effects on the action potential and [Ca2+]i transients are investigated. The presented model can be used by researchers for the interpretation of experimental data and for the developments of mathematical models for other species or for pathological conditions.

Mathematical modeling improves EC50 estimations from classical dose–response curves

“…[25][26][27], and analyzed and reduced to a minimal model with four states [28]. Bondarenko [29] recently presented a compartmentalized mathematical model of bARs ignaling. Other models of interest are concerned with an increased understanding of the mechanisms behind bAR desensitization, as desensitization give rise to overshoots in data.…”

Intermittent Failure Dynamics Characterization

“…It is important to distinguish between β1AR and β2AR activity in simulating HF, because they could have different effects on arrhythmogenesis, as shown by clinical trials and a number of studies [79][80][81]. In this way, the model developed by Bondarenko for mouse myocytes [82] focused on the effects of β1-adrenergic receptor (β1AR) stimulation and represents an initial framework for future developments of cellular models for heart failure. The model elucidates the complex interactions of ionic currents which ultimately lead to a relative modest increase in APD and significant increase in calcium transients when β1AR are stimulated.…”

Distinct physiological effects of β1- and β2-adrenoceptors in mouse ventricular myocytes: insights from a compartmentalized mathematical model

“…Therefore, we developed and explored a compartmentalized mathematical model of mouse ventricular myocytes that includes both the ␤ 1 -and ␤ 2 -adrenergic signaling systems to describe the effects of stimulation of ␤ 1 -and ␤ 2 -ARs on the behavior of cardiac cells. The model is based on the previously developed mathematical model of the ␤ 1 -adrenergic signaling system in mouse ventricular cells, which was extensively verified by the experimental data on the activation of ␤ 1 -ARs (6,27). The model (6) was also recently used by Esprito Santo et al (23) for simulation of the larger susceptibility of isoproterenol-stimulated mouse cardiac cells to DADs with I NaCa overexpression.…”

“…Experimental data on stimulation of ␤ 1 -ARs from different laboratories consistently show a robust increase in protein kinase A (PKA) activity; phosphorylation of ion channels and regulatory and contractile proteins; increase or decrease in ionic currents that shape action potential; and a robust increase in intracellular Ca 2ϩ transient ([Ca 2ϩ ] i ) (see Ref. 6 and references therein). However, the experimental picture of stimulation of ␤ 2 -ARs is less consistent.…”

“…At present, several models of the ␤ 1 -adrenergic signaling system in mammalian cardiac cells have been developed (6,30,34,40,41,60,61). Most of them do not describe the compartmentalization of the signaling pathways, and only two of them include subcellular compartments (caveolae, extracaveolae, cytosol) (6,30). The ␤ 2 -adrenergic signaling system was included only in one model for canine (30); however, its effects on the electrical activity and Ca 2ϩ dynamics were not studied in detail.…”