Can selectivity be functionally modulated in ion channels?

In a two-electrode voltage-clamp study on the rat sympathetic neuron, the properties of the subsynaptic native neuronal AChR (nAChR) in response to the physiologically released ACh were shown to be modified within a few hours after denervation (Sacchi et al., 2008), suggesting that the nAChR ion selectivity switched from preferential permeability to potassium ions to scarce selectivity between K+ and Na+; the changes regarded synaptic, but not extrasynaptic, receptors and revealed an unexpected flexibility of the nicotinic channel in its permeation properties. Subsequently, a number of quite simple experimental procedures in intact ganglia were also shown to produce changes in conductance and ion selectivity properties of the nAChR; unlike denervation, such procedures (resting membrane potential shifts within a voltage range of physiological interest, ionic modifications, and the action of α-bungarotoxin) were very unlikely to acutely produce modifications in nAChR subunit composition or steric conformation (Sacchi et al., 2011). Posttranslational modifications of the channel protein might have occurred, but the consistency of those results with the idea that impermeant Cl− ions might affect cation binding and/or penetration into the pore raised the aforementioned question of whether extrinsic factors might contribute, together with the structural organization of the pore, to determine the permeability and ion selectivity of the channel. Actually, any change in the potential profile along the pore (and/or at its mouths) is bound to affect both the thermodynamic aspects of ion permeation (local field profile and ion binding to sites within the pore) and the kinetic aspects (ease of ion displacement and traveling among subsequent sites). These appear to constitute two distinct factors in determining ion selectivity, but the two aspects are strictly related. The electrical field across the membrane, determined by the membrane potential (Vm), may well be constant and produce a linear change in free energy along the pore. However, the thermodynamic profiles in ion-selective channels display nonlinear variations in the local potential seen by each ion, so that the energetic profile, ΔG(x) = G(x) − G(0) (where 0 refers to the extracellular bulk solution), is not simply a result of the presence of the membrane potential. At equilibrium, the probability for an ion to be located at x, p(x), is proportional to exp(–ΔG(x)/RT); this determines the ratio between forward and backward velocities. As a purely qualitative, numerical example, an arbitrary pore energy profile has been simulated for the Na+ and K+ ions. The profiles for the ions are arbitrarily designed, based on the suggested differential coordination of Na+ and K+ with the charges lining the pore (Nimigean and Allen, 2011). From the same energy profile in the presence of a constant electrical field (Vm = –3RT/zF ≈ –75 mV) the relative occupancy along the pore for Na+ and K+ has been computed, and the resulting permeability derived. It is shown that simple modifications of the profiles by Ca- concentration could account for the observed changes in cation selectivity.