Ionic currents assessed by voltage clamping a myocyte diffusion-reaction model with experimental action potentials

ESCOBAR, ARIEL L; FELICE, JUAN IGNACIO

San Francisco

Encuentro; 62nd Annual Meeting - Biophysical Society; 2018

The Biophysical Society

The timecourse of ventricular action potentials (AP) largely differ between differentmammals. Recently, it was shown that the Ca2+ influx that triggers sarcoplasmicreticulum (SR) Ca2+ release in mouse hearts occurs during AP phase 1and that phase 2 is definedby a Na+ influxthrough the Na+-Ca2+ exchanger (NCX). The likelihood ofthese new ideas was assessed using a mathematical model. Local changes incytosolic and luminal Ca2+ concentration were simulated using adiffusion-reaction framework. Two adjacent sections that represent the myoplasmand the SR lumen were sliced into N diffusional connected sub-compartments. TheCa2+ exchange between cytosol and SR occurs only via ryanodinereceptors (RyR) and SERCA pumps. SR Ca2+ efflux is governed by the Ca2+ gradientand the RyR open probability described by a Markov model having a luminal Ca2+regulation mediated by Ca2+-calsequestrin (CSQ). Ca2+ bufferingin the SR was also definedby CSQ,modeled as an allosteric protein. Myoplasmic Ca2+ buffering was modeledincluding several mobiles (i.e. ATP, Ca2+ indicator) and one fixed buffer (Troponin C). Ca2+ extrusionfrom the cytosol was definedby the NCX. Sarcolemmal Ca2+ influx is mediated by Ca2+ channels thathave voltage and Ca2+ dependent inactivation. In order to minimizethe number of variable parameters, experimentally recorded epicardial APs wereused to electrically drive the model. The parameters of the model were adjustedby comparing the simulated data with Ca2+ transients recordedexperimentally in intact hearts. Using this APvoltage clamp framework we were able to predict that Ca2+ influxto myocytes does occur during phase 1 and that phase 2 is defined by a Na+influx through NCX.