Stabilizing Role of Calcium Store-Dependent Plasma Membrane Calcium Channels in Action-Potential Firing and Intracellular Calcium Oscillations

Abstract

In many biological systems, cells display spontaneous calcium oscillations (CaOs) and repetitive action-potential firing. These phenomena have been described separately by models for intracellular inositol trisphosphate (IP3)-mediated CaOs and for plasma membrane excitability. In this study, we present an integrated model that combines an excitable membrane with an IP3-mediated intracellular calcium oscillator. The IP3 receptor is described as an endoplasmic reticulum (ER) calcium channel with open and close probabilities that depend on the cytoplasmic concentration of IP3 and Ca2+. We show that simply combining this ER model for intracellular CaOs with a model for membrane excitability of normal rat kidney (NRK) fibroblasts leads to instability of intracellular calcium dynamics. To ensure stable long-term periodic firing of action potentials and CaOs, it is essential to incorporate calcium transporters controlled by feedback of the ER store filling, for example, store-operated calcium channels in the plasma membrane. For low IP3 concentrations, our integrated NRK cell model is at rest at -70 mV. For higher IP3 concentrations, the CaOs become activated and trigger repetitive firing of action potentials. At high IP3 concentrations, the basal intracellular calcium concentration becomes elevated and the cell is depolarized near -20 mV. These predictions are in agreement with the different proliferative states of cultures of NRK fibroblasts. We postulate that the stabilizing role of calcium channels and/or other calcium transporters controlled by feedback from the ER store is essential for any cell in which calcium signaling by intracellular CaOs involves both ER and plasma membrane calcium fluxes.

Fast calcium wave propagation mediated by electrically conducted excitation and boosted by CICR

“…In previous studies, we have reported a mathematical model of NRK fibroblasts capturing the basic characteristics (27,28) based on single-cell data (14). This model was obtained by implementation of the dynamics of the membrane ion channels and the intracellular calcium oscillator.…”

“…The key idea of the model (27) is that autocrine and paracrine production of hormones such as PGF 2␣ leads to the production of IP3, which gives rise to IP 3-mediated intracellular calcium oscillations. These IP 3-mediated calcium oscillations cause periodic calcium transients, which open the Cl Ca channels.…”

“…Some recent studies have focused on cell types that have both IP 3 -mediated calcium oscillations and APs, such as in interstitial cells of Cajal (ICC) (4), sinoatrial nodal cells in the heart (31), lymphatic smooth muscle cells (22), and NRK fibroblasts (27). These cell types have the interesting property that the mechanisms of IP 3 -mediated calcium oscillation and AP generation are coupled and interact with each other (28).…”

“…In NRK cells, the major calciumdependent membrane channel type is the calcium-dependent chloride channel (Cl Ca ) with a Nernst potential near Ϫ20 mV. This depolarization may then trigger an AP (6,27). Since electrical coupling through gap junctions is faster than chemical coupling by diffusion of calcium and IP 3 through gap junctions (6,36), the intracellular calcium oscillations between cells are also (indirectly) coupled by the electrical coupling by gap junctions.…”

“…We address these problems using an experimentally verified model for NRK fibroblast cells (27). Contrary to Imtiaz et al (22), we did not include voltage-dependent IP 3 synthesis.…”