General requirement for harvesting antennae at Ca2+ and H+ channels and transporters

Cristián Martínez

doi:10.3389/fnene.2010.00027

Abstract

The production and dissipation of energy in cells is intimately linked to the movement of small molecules in and out of enzymes, channels, and transporters. An analytical model of diffusion was described previously, which was used to estimate local effects of these proteins acting as molecular sources. The present article describes a simple but more general model, which can be used to estimate the local impact of proteins acting as molecular sinks. The results show that the enzymes, transporters, and channels, whose substrates are present at relatively high concentrations like ATP, Na+, glucose, lactate, and pyruvate, do not operate fast enough to deplete their vicinity to a meaningful extent, supporting the notion that for these molecules the cytosol is a well-mixed compartment. One specific consequence of this analysis is that the well-documented cross-talk existing between the Na+/K+ ATPase and the glycolytic machinery should not be explained by putative changes in local ATP concentration. In contrast, Ca2+ and H+ transporters like the Na+/Ca2+ exchanger NCX and the Na+/H+ exchanger NHE, show experimental rates of transport that are two to three orders of magnitude faster than the rates at which the aqueous phase may possibly feed their binding sites. This paradoxical result implies that Ca2+ and H+ transporters do not extract their substrates directly from the bulk cytosol, but from an intermediate “harvesting” compartment located between the aqueous phase and the transport site.

Highlights

The flux of energy in a cell is closely associated with the cycling of molecules between subcellular compartments
Our previous study showed how the steady-state production of molecules by small sources such as enzymes, transporters, and channels determines in some cases the creation of strong local concentration domains and in other cases does not
The aim of the present work was to investigate the mirror problem of how removal of molecules by these proteins may lead to local depletion of substrates. This is a relevant problem for neuroenergetics, for many of the proteins involved in energy transduction are often kept in close proximity to other proteins by lipid microdomains or by protein–protein interactions and may be affected by local concentration changes

Summary

Introduction

The flux of energy in a cell is closely associated with the cycling of molecules between subcellular compartments. One example is the stoichiometric relationship between the cycling of H+ across the inner mitochondrial membrane and the synthesis of ATP Another example is the close relationship between the cycling of Na+ across the plasma membrane and the glycolytic machinery in astrocytes, which couples neuronal activity and local energy production in a phenomenon termed the Astrocyte-to-Neuron Lactate Shuttle (ANLS; Pellerin and Magistretti, 1994). Whereas the most recent formulation of the ANLS hypothesis does not require a strict relationship between Na+ cycling and glucose consumption (Pellerin et al, 2007), such fixed stoichiometry was proposed in a more quantitative model, which assumes that the Na+/K+ ATPase, the pump that extrudes Na+ out of the cell, is fed by glycolytic ATP and not by mitochondrial ATP (Hyder et al, 2006). When molecules are present at higher concentrations, the mixing effect of diffusion impedes the building up of significant local domains, even in the close vicinity of fast ion channels. For ATP, glucose, lactate, pyruvate, Na+, K+, and any other molecules present at bulk concentrations over the micromolar range, the cytosol was shown to behave as a well-mixed compartment

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Results

Conclusion