Activation of Store-Operated Calcium Entry in Airway Smooth Muscle Cells: Insight from a Mathematical Model

Abstract

Intracellular dynamics of airway smooth muscle cells (ASMC) mediate ASMC contraction and proliferation, and thus play a key role in airway hyper-responsiveness (AHR) and remodelling in asthma. We evaluate the importance of store-operated entry (SOCE) in these dynamics by constructing a mathematical model of ASMC signaling based on experimental data from lung slices. The model confirms that SOCE is elicited upon sufficient depletion of the sarcoplasmic reticulum (SR), while receptor-operated entry (ROCE) is inhibited in such conditions. It also shows that SOCE can sustain agonist-induced oscillations in the absence of other influx. SOCE up-regulation may thus contribute to AHR by increasing the oscillation frequency that in turn regulates ASMC contraction. The model also provides an explanation for the failure of the SERCA pump blocker CPA to clamp the cytosolic of ASMC in lung slices, by showing that CPA is unable to maintain the SR empty of . This prediction is confirmed by experimental data from mouse lung slices, and strongly suggests that CPA only partially inhibits SERCA in ASMC.

Mathematical investigation of IP3-dependent calcium dynamics in astrocytes

“…Open-cell calcium dynamics have been the focus of numerous research publications (Sneyd et al, 2004; Ullah et al, 2006; De Pittà et al, 2009; Croisier et al, 2013), and have been reviewed in Falcke (2004), Dupont (2014), and Dupont et al (2016). Building off this previous work, this paper analyzes the calcium dynamics stemming from a unique and astrocyte-specific combination of calcium fluxes and external stimulation.…”

“…In addition, the models parameters were chosen in order to capture qualitative and quantitative behavior from astrocyte-specific experiments. Further, while there has been a recent focus of some mathematical models to investigate the role of SOC channels in calcium dynamics, the fields understanding of this channel is still incomplete (Liu et al, 2010; Croisier et al, 2013). In this work, we provide a detailed analysis of this flux and how the underlying dynamical structure is dependent on this quiet, yet influential channel.…”

“…1. Specifically, we use the Li-Rinzel IP 3 receptor model to capture the calcium dynamics through the IP 3 R channel (Li and Rinzel, 1996), which is governed by the following equations $$\begin{array}{c}{J}_{\text{IP}3\mathrm{normalR}}false(c,c_{\mathit{\text{ER}}},pfalse)={\upsilon }_{\text{IP}3\mathrm{normalR}}{m}_{\infty }{false(pfalse)}^3{n}_{\infty }{false(c,pfalse)}^{3}false(c_{\mathit{\text{ER}}}-cfalse),\\ \frac{\mathit{\text{dh}}}{\mathit{\text{dt}}}=\frac{h_{\infty }false(c,pfalse)-h}{{\tau }_{h}false(c,pfalse)},\end{array}$$ where $$m_{\infty }(p)=\frac{p}{p+d_1},n_{\infty }(c)=\frac{c}{c+d_5},$$ and $$\begin{array}{c}{\tau }_{h}false(p,cfalse)=\frac{1}{a_{2}false(Q_{2}false(pfalse)+cfalse)},h_{\infty }false(p,cfalse)=\frac{Q_{2}false(pfalse)}{Q_{2}false(pfalse)+c},\\ Q_{2}false(pfalse)=d_2\left(\frac{p+d_1}{P+d_3}\right).\end{array}$$ The SERCA and PMCA pumps are both model as Hill functions, the forms found in Cao et al (2014) and Croisier et al (2013) respectively, and are given by the equations, $$J_{\text{SERCA}}(c)={\upsilon }_{\text{SERCA}}\frac{c^{1.75}}{c^{1.75}+k_{\text{SERCA}}^{1.75}},$$ and …”

Ryanodine Receptor Sensitization Results in Abnormal Calcium Signaling in Airway Smooth Muscle Cells

“…The model is an extension of previous work [17]. In brief, the dynamics of c =[Ca 2+ ]i and cs =[Ca 2+ ]SR are governed by:…”

“…This role for RyR sensitivity can be explored experimentally with compounds such as caffeine that increase the open probability of RyR to [Ca 2+ ]SR and [Ca 2+ ]i [15,16]. Therefore, in this work, we integrate both IP3R and RyR dynamics into an extension of our previous mathematical model of Ca 2+ dynamics in ASMC [17] and experimentally test the predictions of this model. The consequences of RyR sensitization on ASMC Ca 2+ dynamics is evaluated in the absence and presence of agonist stimulation.…”