Putative resolution of the EEEE selectivity paradox in L-type Ca2+ and bacterial Na+ biological ion channels

I Kh Kaufman,P V E Mcclintock,W A T Gibby,R S Eisenberg,D G Luchinsky

doi:10.1088/1742-5468/2016/05/054027

Abstract

The highly selective permeation of ions through biological ion channels can be described and explained in terms of fluctuational dynamics under the influence of powerful electrostatic forces. Hence valence selectivity, e.g. between Ca2+ and Na+ in calcium and sodium channels, can be described in terms of ionic Coulomb blockade, which gives rise to distinct conduction bands and stop-bands as the fixed negative charge Qf at the selectivity filter of the channel is varied. This picture accounts successfully for a wide range of conduction phenomena in a diversity of ion channels. A disturbing anomaly, however, is that what appears to be the same electrostatic charge and structure (the so-called EEEE motif) seems to select Na+ conduction in bacterial channels but Ca2+ conduction in mammalian channels. As a possible resolution of this paradox it is hypothesised that an additional charged protein residue on the permeation path of the mammalian channel increases by e, thereby altering the selectivity from Na+ to Ca2+. Experiments are proposed that will enable the hypothesis to be tested.

Highlights

Biological ion channels [1] are natural nanopores through cellular membranes
We generalized the electrostatic analysis of the multi-ion energetics of conduction bands [23] by introducing an ionic Coulomb blockade model of conduction and selectivity in biological ion channels thereby bringing them into the context of mesoscopic phenomena [17, 25]
In our previous papers we identified M1 with the L-type calcium channel assuming that protonation might account for the charge discrepancy

Summary

Introduction

Biological ion channels [1] are natural nanopores through cellular membranes. They provide for the fast and highly selective permeation of physiologically important ions like Na+, K+ and Ca2+. Mutation studies [3, 7,8,9] and simulations [10,11,12,13,14,15] show that the fixed charge Qf provided by the residues is a determinant of the channel’s conductivity and valence selectivity Both nanopores [16] and ion channels [17] exhibit the phenomenon of ionic Coulomb blockade, closely analogous to electronic Coulomb blockade in mesoscopic systems [18,19,20].

Generic model of calcium channel

Coulomb blockade model of ionic permeation

Mechanisms of blockade and permeation

Proposed resolution of the EEEE Paradox in calcium channels

Conclusions