Emergent activity, heterogeneity, and robustness in a calcium feedback model of the sinoatrial node

Moise, Nicolae; Weinberg, Seth H.

doi:10.1016/j.bpj.2023.03.024

Cited by 7 publications

(16 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In [4, 8], the protein regulation model is given in the form 1 Here, c is the cytosolic calcium concentration, c * is the target calcium concentration, g is the conductance of the considered type of ion channel, and τ r and τ g are time constants.…”

Section: Supplementary Informationmentioning

confidence: 99%

“…The simulation is started from n = m = 0.1 in exactly the same manner as in Figure 1 in the paper. We let τ m = 400 mMms (like in the paper) and vary τ n between 100 ms and 10,000 ms. For comparison, the values τ n = 1000 ms was used in [8]. We observe that all the considered values of τ n provide almost identical solutions.…”

Section: Supplementary Informationmentioning

confidence: 99%

“…Furthermore, n is the scaling factor for the number of L-type calcium channels in the cell membrane. In the paper, we consider two alternative models for this factor, one model directly based on [4, 8] given by (S9)–(S10) and one updated model described in the main paper and repeated in Section S4.4.…”

Section: Supplementary Informationmentioning

confidence: 99%

“…Their modeling framework has found applications beyond the original scope. Recently, Moise and Weinberg [8] adapted this model to analyze ion conductances within the cells of the Sinoatrial node, further demonstrating the model’s relevance and utility in understanding the complex dynamics of ion channel regulation; see also [9].…”

Section: Introductionmentioning

confidence: 99%

“…One version of the model for dynamic ion channel expression can be written in the following form, A description of how the model from [4, 8] can be rewritten to the form (1)–(2) is provided in the Supplementary Information (SI). Here, τ m and τ n are time constants, c is the cytosolic calcium concentration, and c * is the target level of the cytosolic calcium concentration.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Do calcium channel blockers applied to cardiomyocytes cause increased channel expression resulting in reduced efficacy?

Jæger,

Charwat,

Wall

et al. 2023

Preprint

View full text Add to dashboard Cite

In the initial hours following the application of the calcium channel blocker (CCB) nifedipine to microtissues consisting of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we observe notable variations in the drug’s efficacy. Here, we investigate the possibility that these temporal changes in CCB effects are associated with adaptations in the expression of calcium ion channels in cardiomyocyte membranes. To explore this, we employ a recently developed mathematical model that delineates the regulation of calcium ion channel expression by intracellular calcium concentrations. According to the model, a decline in intracellular calcium levels below a certain target level triggers an upregulation of calcium ion channels. Such an upregulation, if instigated by a CCB, would then counteract the drug’s inhibitory effect on calcium currents. We assess this hypothesis using time-dependent measurements of hiPSC-CMs dynamics and by refining an existing mathematical model of myocyte action potentials incorporating the dynamic nature of the number of calcium ion channels. The revised model forecasts that the CCB-induced reduction in intracellular calcium concentrations leads to a subsequent increase in calcium ion channel expression, thereby attenuating the drug’s overall efficacy. The data and fit models suggests that dynamic changes in cardiac cells in the presence of CCBs may be explainable by induced changes in protein expression, and that this may lead to challenges in understanding calcium based drug effects on the heart unless timings of applications are carefully considered.

show abstract