Mouse cardiac sarcolemma Ca2+ fluxes assessed by an AP voltage clamping diffusion-reaction model

FELICE, JUAN IGNACIO; MATTIAZZI, RAMONA ALICIA; ESCOBAR, ARIEL L

Mendoza

Encuentro; XXIV Scientific Meeting of the Latin American Section of the ISHR - 2017; 2017

International Society for Heart Research (ISHR)

Thetime course of ventricular action potentials (AP) largely differ betweendifferent mammals. The increase in the use of transgenesis has made the mousean ideal model to study cardiac function. Recently, it was shown that the Ca2+influx that triggers sarcoplasmic reticulum (SR) Ca2+ release in mousehearts occurs during AP phase 1 and that phase 2 is defined by a Na+influx through Na+/Ca2+ exchange (NCX). The likelihood ofthese new ideas was assessed using a mathematical model. Local changes in cytosolicand luminal Ca2+ concentration were simulated using adiffusion-reaction framework that models Ca2+ dynamics. Two adjacentsections that represent the myoplasm and the SR lumen were sliced into Ndiffusional connected sub-compartments. Ca2+ exchange between cytosoland SR occurs only via ryanodine receptors (RyR) and SERCA pumps. SR Ca2+efflux is governed by the Ca2+ gradient and the RyR open probability describedby a Markov model having a luminal Ca2+ regulation mediated by Ca2+ calsequestrin(CSQ). Ca2+ buffering in the SR was also defined by CSQ, modeled asan allosteric protein. Myoplasmic Ca2+ buffering was modeledincluding several mobile (i.e. ATP, Ca2+ indicator) and one fixedbuffer (Troponin C). Ca2+ extrusion from the cytosol was defined bythe NCX. Sarcolemmal Ca2+ influx is mediated by Ca2+channels that have voltage andCa2+ dependent inactivations. All theequations were numerically integrated using Euler. The initial values werecalculated using a Q-matrix and a Neumann?s boundary condition was imposed. Inorder to minimize the number of variable parameters, experimentally recordedepicardial AP were used to electrically drive the model. The parameters of themodel were adjusted by comparing the simulated data with Ca2+transients recorded experimentally in intact hearts. Using this AP voltage clampframework we were able to predict that Ca2+ influx to myocytes doesoccur during phase 1 and that phase 2 is defined by a Na+ influxthrough NCX.