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Mathematical model of mouse embryonic cardiomyocyte excitation-contraction coupling.

Korhonen T, Rapila R, Tavi P - J. Gen. Physiol. (2008)

Bottom Line: We further validate our model by simulating the effect of genetic modifications on the hyperpolarization-activated current, NCX, and the SR Ca(2+) buffer protein calreticulin.In these simulations, the model produces a similar functional alteration to that observed previously in the genetically engineered mice, and thus provides mechanistic explanations for the cardiac phenotypes of these animals.In general, this study presents the first model explaining the underlying cellular mechanism for the origin and the regulation of the heartbeat in early embryonic cardiomyocytes.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedicine, Department of Physiology and Biocenter Oulu, University of Oulu, 90014 Oulu, Finland.

ABSTRACT
Excitation-contraction (E-C) coupling is the mechanism that connects the electrical excitation with cardiomyocyte contraction. Embryonic cardiomyocytes are not only capable of generating action potential (AP)-induced Ca(2+) signals and contractions (E-C coupling), but they also can induce spontaneous pacemaking activity. The spontaneous activity originates from spontaneous Ca(2+) releases from the sarcoplasmic reticulum (SR), which trigger APs via the Na(+)/Ca(2+) exchanger (NCX). In the AP-driven mode, an external stimulus triggers an AP and activates voltage-activated Ca(2+) intrusion to the cell. These complex and unique features of the embryonic cardiomyocyte pacemaking and E-C coupling have never been assessed with mathematical modeling. Here, we suggest a novel mathematical model explaining how both of these mechanisms can coexist in the same embryonic cardiomyocytes. In addition to experimentally characterized ion currents, the model includes novel heterogeneous cytosolic Ca(2+) dynamics and oscillatory SR Ca(2+) handling. The model reproduces faithfully the experimentally observed fundamental features of both E-C coupling and pacemaking. We further validate our model by simulating the effect of genetic modifications on the hyperpolarization-activated current, NCX, and the SR Ca(2+) buffer protein calreticulin. In these simulations, the model produces a similar functional alteration to that observed previously in the genetically engineered mice, and thus provides mechanistic explanations for the cardiac phenotypes of these animals. In general, this study presents the first model explaining the underlying cellular mechanism for the origin and the regulation of the heartbeat in early embryonic cardiomyocytes.

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The current–voltage relations of the ion currents in the E9-E11 mouse cardiomyocytes and in the mathematical model. (A) INCX, (B) If (the activation time constant is also shown), (C) INa, (D) IK1 and IKDR, and (E) T- and L-type calcium channels (top right panel). In each case, red or blue symbols denote the experimentally defined features of the ion currents that were adopted into the model (black solid lines). The representative recordings are shown in the left column of each panel.
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fig2: The current–voltage relations of the ion currents in the E9-E11 mouse cardiomyocytes and in the mathematical model. (A) INCX, (B) If (the activation time constant is also shown), (C) INa, (D) IK1 and IKDR, and (E) T- and L-type calcium channels (top right panel). In each case, red or blue symbols denote the experimentally defined features of the ion currents that were adopted into the model (black solid lines). The representative recordings are shown in the left column of each panel.

Mentions: The models of the NCX (Luo and Rudy, 1994), If (Pandit et al., 2001), fast Na+ current (INa) (Bondarenko et al., 2004), slowly activated delayed rectifier K+ current (IKDR) (Dokos et al., 1996), time-independent background K+ current (IK1) (Dokos et al., 1996), L-type Ca2+ current (ICaL) (Bondarenko et al., 2004), and T-type Ca2+ current (ICaT) (Dokos et al., 1996) were fitted to our whole cell voltage-clamp data (Fig. 2). The fitted conductances were scaled from T = 25°C (in Fig. 2) to T = 34°C with Q10 = 1.35 (Hart, 1983; Hille, 2001), except Q10-NCX = 1.6 (Debetto et al., 1990; Puglisi et al., 1996; Shannon et al., 2004) and Q10-ICaL = 1.8 (Puglisi et al., 1999; Shannon et al., 2004). The If time constant was scaled with Q10 = 3 (Hart, 1983; Hille, 2001). As described previously, the fitting of the INa was based partly on the AP upstroke properties (Bondarenko et al., 2004). The background Ca2+ current is modeled as a linear ohmic current and fitted to obtain a physiologically correct diastolic [Ca2+] (∼0.1–0.2 μM). The model of the NaK-ATPase (Luo and Rudy, 1994) was fitted to maintain physiologically correct intracellular Na+ and K+ concentrations (∼14 and ∼140 mM, respectively). The ion currents change the cytosolic [Ca2+] below the SL and the cytosolic common pool [Na+] and [K+].


Mathematical model of mouse embryonic cardiomyocyte excitation-contraction coupling.

Korhonen T, Rapila R, Tavi P - J. Gen. Physiol. (2008)

The current–voltage relations of the ion currents in the E9-E11 mouse cardiomyocytes and in the mathematical model. (A) INCX, (B) If (the activation time constant is also shown), (C) INa, (D) IK1 and IKDR, and (E) T- and L-type calcium channels (top right panel). In each case, red or blue symbols denote the experimentally defined features of the ion currents that were adopted into the model (black solid lines). The representative recordings are shown in the left column of each panel.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2553388&req=5

fig2: The current–voltage relations of the ion currents in the E9-E11 mouse cardiomyocytes and in the mathematical model. (A) INCX, (B) If (the activation time constant is also shown), (C) INa, (D) IK1 and IKDR, and (E) T- and L-type calcium channels (top right panel). In each case, red or blue symbols denote the experimentally defined features of the ion currents that were adopted into the model (black solid lines). The representative recordings are shown in the left column of each panel.
Mentions: The models of the NCX (Luo and Rudy, 1994), If (Pandit et al., 2001), fast Na+ current (INa) (Bondarenko et al., 2004), slowly activated delayed rectifier K+ current (IKDR) (Dokos et al., 1996), time-independent background K+ current (IK1) (Dokos et al., 1996), L-type Ca2+ current (ICaL) (Bondarenko et al., 2004), and T-type Ca2+ current (ICaT) (Dokos et al., 1996) were fitted to our whole cell voltage-clamp data (Fig. 2). The fitted conductances were scaled from T = 25°C (in Fig. 2) to T = 34°C with Q10 = 1.35 (Hart, 1983; Hille, 2001), except Q10-NCX = 1.6 (Debetto et al., 1990; Puglisi et al., 1996; Shannon et al., 2004) and Q10-ICaL = 1.8 (Puglisi et al., 1999; Shannon et al., 2004). The If time constant was scaled with Q10 = 3 (Hart, 1983; Hille, 2001). As described previously, the fitting of the INa was based partly on the AP upstroke properties (Bondarenko et al., 2004). The background Ca2+ current is modeled as a linear ohmic current and fitted to obtain a physiologically correct diastolic [Ca2+] (∼0.1–0.2 μM). The model of the NaK-ATPase (Luo and Rudy, 1994) was fitted to maintain physiologically correct intracellular Na+ and K+ concentrations (∼14 and ∼140 mM, respectively). The ion currents change the cytosolic [Ca2+] below the SL and the cytosolic common pool [Na+] and [K+].

Bottom Line: We further validate our model by simulating the effect of genetic modifications on the hyperpolarization-activated current, NCX, and the SR Ca(2+) buffer protein calreticulin.In these simulations, the model produces a similar functional alteration to that observed previously in the genetically engineered mice, and thus provides mechanistic explanations for the cardiac phenotypes of these animals.In general, this study presents the first model explaining the underlying cellular mechanism for the origin and the regulation of the heartbeat in early embryonic cardiomyocytes.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedicine, Department of Physiology and Biocenter Oulu, University of Oulu, 90014 Oulu, Finland.

ABSTRACT
Excitation-contraction (E-C) coupling is the mechanism that connects the electrical excitation with cardiomyocyte contraction. Embryonic cardiomyocytes are not only capable of generating action potential (AP)-induced Ca(2+) signals and contractions (E-C coupling), but they also can induce spontaneous pacemaking activity. The spontaneous activity originates from spontaneous Ca(2+) releases from the sarcoplasmic reticulum (SR), which trigger APs via the Na(+)/Ca(2+) exchanger (NCX). In the AP-driven mode, an external stimulus triggers an AP and activates voltage-activated Ca(2+) intrusion to the cell. These complex and unique features of the embryonic cardiomyocyte pacemaking and E-C coupling have never been assessed with mathematical modeling. Here, we suggest a novel mathematical model explaining how both of these mechanisms can coexist in the same embryonic cardiomyocytes. In addition to experimentally characterized ion currents, the model includes novel heterogeneous cytosolic Ca(2+) dynamics and oscillatory SR Ca(2+) handling. The model reproduces faithfully the experimentally observed fundamental features of both E-C coupling and pacemaking. We further validate our model by simulating the effect of genetic modifications on the hyperpolarization-activated current, NCX, and the SR Ca(2+) buffer protein calreticulin. In these simulations, the model produces a similar functional alteration to that observed previously in the genetically engineered mice, and thus provides mechanistic explanations for the cardiac phenotypes of these animals. In general, this study presents the first model explaining the underlying cellular mechanism for the origin and the regulation of the heartbeat in early embryonic cardiomyocytes.

Show MeSH
Related in: MedlinePlus