Sodium Permeability of a Cloned Small-Conductance Calcium-Activated Potassium Channel

Small-conductance Ca2+-activated potassium channels (SKCa channels) are heteromeric complexes of pore-forming main subunits and constitutively bound calmodulin. SKCa channels in neuronal cells are activated by intracellular Ca2+ that increases during action potentials, and their ionic currents have been considered to underlie neuronal afterhyperpolarization. However, the ion selectivity of neuronal SKCa channels has not been rigorously investigated. In this study, we determined the monovalent cation selectivity of a cloned rat SKCa channel, rSK2, using heterologous expression and electrophysiological measurements. When extracellular K+ was replaced isotonically with Na+, ionic currents through rSK2 reversed at significantly more depolarized membrane potentials than the value expected for a Nernstian relationship for K+. We then determined the relative permeability of rSK2 for monovalent cations and compared them with those of the intermediate- and large-conductance Ca2+-activated K+ channels, IKCa and BKCa channels. The relative permeability of the rSK2 channel was determined as K+(1.0)>Rb+(0.80)>NH4+(0.19)≈Cs+(0.19)>Li+(0.14)>Na+(0.12), indicating substantial permeability of small ions through the channel. Although a mutation near the selectivity filter mimicking other K+-selective channels influenced the size-selectivity for permeant ions, Na+ permeability of rSK2 channels was still retained. Since the reversal potential of endogenous SKCa current is determined by Na+ permeability in a physiological ionic environment, the ion selectivity of native SKCa channels should be reinvestigated and their in vivo roles may need to be restated.