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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Modeling action potential generation and propagation in NRK fibroblasts

¹Institute "Carlos I" for Theoretical and Computational Physics and Department of Electromagnetism and Matter Physics, University of Granada, E-18071 Granada, Spain; ²Department of Medical Physics and Biophysics, University of Nijmegen, 6525 EZ Nijmegen; Departments of ³Cell Biology and ⁴Cellular Animal Physiology, Institute of Cellular Signaling, University of Nijmegen, 6525 ED Nijmegen; and ⁵Department of Physiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Submitted 28 May 2003 ; accepted in final form 10 May 2004

Normal rat kidney (NRK) fibroblasts change their excitability properties through the various stages of cell proliferation. The present mathematical model has been developed to explain excitability of quiescent (serum deprived) NRK cells. It includes as cell membrane components, on the basis of patch-clamp experiments, an inwardly rectifying potassium conductance (G_Kir), an L-type calcium conductance (G_CaL), a leak conductance (G_leak), an intracellular calcium-activated chloride conductance [G_Cl(Ca)], and a gap junctional conductance (G_gj), coupling neighboring cells in a hexagonal pattern. This membrane model has been extended with simple intracellular calcium dynamics resulting from calcium entry via G_CaL channels, intracellular buffering, and calcium extrusion. It reproduces excitability of single NRK cells and cell clusters and intercellular action potential (AP) propagation in NRK cell monolayers. Excitation can be evoked by electrical stimulation, external potassium-induced depolarization, or hormone-induced intracellular calcium release. Analysis shows the roles of the various ion channels in the ultralong (30 s) NRK cell AP and reveals the particular role of intracellular calcium dynamics in this AP. We support our earlier conclusion (De Roos A, Willems PH, van Zoelen EJ, and Theuvenet AP. Am J Physiol Cell Physiol 273: C1900–C1907, 1997) that AP generation and propagation may act as a rapid mechanism for the propagation of intracellular calcium waves, thus contributing to fast intercellular calcium signaling. The present model serves as a starting point to further analyze excitability changes during contact inhibition and cell transformation.

Hodgkin-Huxley model; intracellular calcium dynamics; L-type calcium conductance; inward rectifier; calcium-activated chloride conductance; gap junctional coupling

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