Modelling intracellular H+ ion diffusion

Intracellular pH, an important modulator of cell function, is regulated by plasmalemmal proteins that transport H+, or its equivalent, into or out of the cell. The pH(i) is also stabilised by high-capacity, intrinsic buffering on cytoplasmic proteins, oligopeptides and other solutes, and by the extrinsic CO2/HCO3- (carbonic) buffer. As mobility of these buffers is lower than for the H+ ion, they restrict proton diffusion. In this paper we use computational approaches, based on the finite difference and finite element methods (FDM and FEM, respectively), for analysing the spatio-temporal behaviour of [H+] when it is locally perturbed. We analyse experimental data obtained for various cell-types (cardiac myocytes, duodenal enterocytes, molluscan neurons) where pHi has been imaged confocally using intracellular pH-sensitive dyes. We design mathematical algorithms to generate solutions for two-dimensional diffusion that fit data in terms of an apparent intracellular H+ diffusion coefficient; D-H(app). The models are used to explore how the spatial distribution of [H+](i) is affected by membrane H+-equivalent transport and by cell geometry. We then develop a mechanistic model, describing spatio-temporal changes of [H+](i) in a cardiac ventricular myocyte in terms of H+-shuttling on mobile buffers and H+-anchoring on fixed buffers. We also discuss how modelling may include the effects of extrinsic carbonic-buffering. Overall, our computational approach provides a framework for future analyses of the physiological consequences of pHi nonuniformity. (C) 2003 Elsevier Ltd: All rights reserved.