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

J. M. A. M. Kusters ^*, M. M. Dernison , W. P. M. van Meerwijk , D. L. Ypey  , A. P. R. Theuvenet  and C. C. A. M. Gielen ^*

^* Department of Medical Physics and Biophysics, and Department of Cell Biology, Institute for Neuroscience, Radboud University Nijmegen, Nijmegen, The Netherlands; and Department of Physiology, Leiden University Medical Center, Leiden, The Netherlands

Correspondence: Address reprint requests to C. C. A. M. Gielen, Dept. of Medical Physics and Biophysics, Institute for Neuroscience, Radboud University Nijmegen, Geert Grooteplein 21, 6525 EZ Nijmegen, The Netherlands. Tel.: 31-24-361-4242; Fax: 31-24-354-1435; E-mail: s.gielen{at}science.ru.nl.

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.

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