The Anomalous Mole Fraction Effect in Calcium Channels: The Ryanodine Receptor Case Study

Abstract

The origin of the anomalous mole fraction effect (AMFE) in calcium channels is explored with an ion permeation model of the ryanodine receptor (RyR) calcium channel. This model predicted and experiments verified new AMFEs in RyR. In mole fraction experiments, conductance is measured in mixtures of two ion species (X and Y) as their relative amounts (mole fractions) vary. This curve can have a mimimum (an AMFE). The traditional interpretation of the AMFE is that multiple ions move through the pore in a single file. Nonlinear mole fraction curves without minima are generally interpreted as X displacing Y from the pore in proportion larger than its bath mole fraction (preferential selectivity). We find that the AMFE is also caused by preferential selectivity of X over Y if they have similar conductances. This is a prediction for any channel. Preferential selectivity causes the resistances to current flow in the baths, channel vestibules, and selectivity filter to change differently with mole fraction. This resistors-in-series model provides a fundamentally different explanation of the AMFE that does not require single filing or multiple occupancy. The success of the resistors-in-series model to predict AMFEs in RyR shows that the traditional model should be reconsidered for calcium channels.