The logic of ionic homeostasis: Cations are for voltage, but not for volume

Neuronal activity is associated with transmembrane ionic redistribution, which can lead to an osmotic imbalance. Accordingly, activity-dependent changes of the membrane potential are sometimes accompanied by changes in intracellular and/or extracellular volume. Experimental data that include distributions of ions and volume during neuronal activity are rare and rather inconsistent partly due to the technical difficulty of performing such measurements. However, progress in understanding the interrelations among ions, voltage and volume has been achieved recently by computational modelling, particularly "charge-difference" modelling. In this work a charge-difference computational model was used for further understanding of the specific roles for cations and anions. Our simulations show that without anion conductances the transmembrane movements of cations are always osmotically balanced, regardless of the stoichiometry of the pump or the ratio of Na+ and K+ conductances. Yet any changes in cation conductance or pump activity are associated with changes of the membrane potential, even when a hypothetically electroneutral pump is used in calculations and K+ and Na+ conductances are equal. On the other hand, when a Cl- conductance is present, the only way to keep the Cl-equilibrium potential in accordance with the changed membrane potential is to adjust cell volume. Importantly, this voltage-evoked Cl--dependent volume change does not affect intracellular cation concentrations or the amount of energy that is necessary to support the system. Taking other factors into consideration (i.e. the presence of internal impermeant poly-anions, the activity of cation-Cl- cotransporters, and the buildup of intra- and extracellular osmolytes, both charged and electroneutral) adds complexity, but does not change the main principles.