Toward an integrative computational model of the guinea pig cardiac myocyte

Laura Doyle Gauthier, Joseph L. Greenstein, Raimond Winslow

Research output: Contribution to journalArticle

Abstract

The local control theory of excitation-contraction (EC) coupling asserts that regulation of calcium (Ca 2+) release occurs at the nanodomain level, where openings of single L-type Ca 2+ channels (LCCs) trigger openings of small clusters of ryanodine receptors (RyRs) co-localized within the dyad. A consequence of local control is that the whole-cell Ca 2+ transient is a smooth continuous function of influx of Ca 2+ through LCCs. While this so-called graded release property has been known for some time, its functional importance to the integrated behavior of the cardiac ventricular myocyte has not been fully appreciated. We previously formulated a biophysically based model, in which LCCs and RyRs interact via a coarse-grained representation of the dyadic space. The model captures key features of local control using a low-dimensional system of ordinary differential equations. Voltage-dependent gain and graded Ca 2+ release are emergent properties of this model by virtue of the fact that model formulation is closely based on the sub-cellular basis of local control. In this current work, we have incorporated this graded release model into a prior model of guinea pig ventricular myocyte electrophysiology, metabolism, and isometric force production. The resulting integrative model predicts the experimentally observed causal relationship between action potential (AP) shape and timing of Ca 2+ and force transients, a relationship that is not explained by models lacking the graded release property. Model results suggest that even relatively subtle changes in AP morphology that may result, for example, from remodeling of membrane transporter expression in disease or spatial variation in cell properties, may have major impact on the temporal waveform of Ca 2+ transients, thus influencing tissue level electromechanical function.

Original languageEnglish (US)
Article numberArticle 244
JournalFrontiers in Physiology
Volume3 JUL
DOIs
StatePublished - 2012

Fingerprint

Ryanodine Receptor Calcium Release Channel
Cardiac Myocytes
Action Potentials
Guinea Pigs
Excitation Contraction Coupling
Membrane Transport Proteins
Electrophysiology
Muscle Cells
Calcium

Keywords

  • Calcium cycling, calcium-induced calcium-release, cardiac myocyte, computational model, excitation-contraction coupling, mitochondrial energetics

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Toward an integrative computational model of the guinea pig cardiac myocyte. / Gauthier, Laura Doyle; Greenstein, Joseph L.; Winslow, Raimond.

In: Frontiers in Physiology, Vol. 3 JUL, Article 244, 2012.

Research output: Contribution to journalArticle

@article{fd4f7dab771b45b094734061da848327,
title = "Toward an integrative computational model of the guinea pig cardiac myocyte",
abstract = "The local control theory of excitation-contraction (EC) coupling asserts that regulation of calcium (Ca 2+) release occurs at the nanodomain level, where openings of single L-type Ca 2+ channels (LCCs) trigger openings of small clusters of ryanodine receptors (RyRs) co-localized within the dyad. A consequence of local control is that the whole-cell Ca 2+ transient is a smooth continuous function of influx of Ca 2+ through LCCs. While this so-called graded release property has been known for some time, its functional importance to the integrated behavior of the cardiac ventricular myocyte has not been fully appreciated. We previously formulated a biophysically based model, in which LCCs and RyRs interact via a coarse-grained representation of the dyadic space. The model captures key features of local control using a low-dimensional system of ordinary differential equations. Voltage-dependent gain and graded Ca 2+ release are emergent properties of this model by virtue of the fact that model formulation is closely based on the sub-cellular basis of local control. In this current work, we have incorporated this graded release model into a prior model of guinea pig ventricular myocyte electrophysiology, metabolism, and isometric force production. The resulting integrative model predicts the experimentally observed causal relationship between action potential (AP) shape and timing of Ca 2+ and force transients, a relationship that is not explained by models lacking the graded release property. Model results suggest that even relatively subtle changes in AP morphology that may result, for example, from remodeling of membrane transporter expression in disease or spatial variation in cell properties, may have major impact on the temporal waveform of Ca 2+ transients, thus influencing tissue level electromechanical function.",
keywords = "Calcium cycling, calcium-induced calcium-release, cardiac myocyte, computational model, excitation-contraction coupling, mitochondrial energetics",
author = "Gauthier, {Laura Doyle} and Greenstein, {Joseph L.} and Raimond Winslow",
year = "2012",
doi = "10.3389/fphys.2012.00244",
language = "English (US)",
volume = "3 JUL",
journal = "Frontiers in Physiology",
issn = "1664-042X",
publisher = "Frontiers Research Foundation",

}

TY - JOUR

T1 - Toward an integrative computational model of the guinea pig cardiac myocyte

AU - Gauthier, Laura Doyle

AU - Greenstein, Joseph L.

AU - Winslow, Raimond

PY - 2012

Y1 - 2012

N2 - The local control theory of excitation-contraction (EC) coupling asserts that regulation of calcium (Ca 2+) release occurs at the nanodomain level, where openings of single L-type Ca 2+ channels (LCCs) trigger openings of small clusters of ryanodine receptors (RyRs) co-localized within the dyad. A consequence of local control is that the whole-cell Ca 2+ transient is a smooth continuous function of influx of Ca 2+ through LCCs. While this so-called graded release property has been known for some time, its functional importance to the integrated behavior of the cardiac ventricular myocyte has not been fully appreciated. We previously formulated a biophysically based model, in which LCCs and RyRs interact via a coarse-grained representation of the dyadic space. The model captures key features of local control using a low-dimensional system of ordinary differential equations. Voltage-dependent gain and graded Ca 2+ release are emergent properties of this model by virtue of the fact that model formulation is closely based on the sub-cellular basis of local control. In this current work, we have incorporated this graded release model into a prior model of guinea pig ventricular myocyte electrophysiology, metabolism, and isometric force production. The resulting integrative model predicts the experimentally observed causal relationship between action potential (AP) shape and timing of Ca 2+ and force transients, a relationship that is not explained by models lacking the graded release property. Model results suggest that even relatively subtle changes in AP morphology that may result, for example, from remodeling of membrane transporter expression in disease or spatial variation in cell properties, may have major impact on the temporal waveform of Ca 2+ transients, thus influencing tissue level electromechanical function.

AB - The local control theory of excitation-contraction (EC) coupling asserts that regulation of calcium (Ca 2+) release occurs at the nanodomain level, where openings of single L-type Ca 2+ channels (LCCs) trigger openings of small clusters of ryanodine receptors (RyRs) co-localized within the dyad. A consequence of local control is that the whole-cell Ca 2+ transient is a smooth continuous function of influx of Ca 2+ through LCCs. While this so-called graded release property has been known for some time, its functional importance to the integrated behavior of the cardiac ventricular myocyte has not been fully appreciated. We previously formulated a biophysically based model, in which LCCs and RyRs interact via a coarse-grained representation of the dyadic space. The model captures key features of local control using a low-dimensional system of ordinary differential equations. Voltage-dependent gain and graded Ca 2+ release are emergent properties of this model by virtue of the fact that model formulation is closely based on the sub-cellular basis of local control. In this current work, we have incorporated this graded release model into a prior model of guinea pig ventricular myocyte electrophysiology, metabolism, and isometric force production. The resulting integrative model predicts the experimentally observed causal relationship between action potential (AP) shape and timing of Ca 2+ and force transients, a relationship that is not explained by models lacking the graded release property. Model results suggest that even relatively subtle changes in AP morphology that may result, for example, from remodeling of membrane transporter expression in disease or spatial variation in cell properties, may have major impact on the temporal waveform of Ca 2+ transients, thus influencing tissue level electromechanical function.

KW - Calcium cycling, calcium-induced calcium-release, cardiac myocyte, computational model, excitation-contraction coupling, mitochondrial energetics

UR - http://www.scopus.com/inward/record.url?scp=84866458466&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866458466&partnerID=8YFLogxK

U2 - 10.3389/fphys.2012.00244

DO - 10.3389/fphys.2012.00244

M3 - Article

VL - 3 JUL

JO - Frontiers in Physiology

JF - Frontiers in Physiology

SN - 1664-042X

M1 - Article 244

ER -