Zn2+ modulation of neuronal transient K+ current: Fast and selective binding to the deactivated channels

Modulation of voltage-dependent transient K+ currents (A type K+ or K-A cur rent) by Zn2+ was studied in rat hippocampal neurons by the whole-cell patc h-clamp technique. It is found that Zn2+ selectively binds to the resting ( deactivated or closed) K-A channels with a dissociation constant (K-d) of s imilar to 3 mu M, whereas the affinity between Zn2+ and the inactivated K-A channels is 1000-fold lower. Zn2+ therefore produces a concentration-depen dent shift of the K-A channel inactivation curve and enhances the K-A curre nt elicited from relatively positive holding potentials, It is also found t hat the kinetics of Zn2+ action are fast enough to compete with the transit ion rates between different gating states of the channel. The rapid and sel ective binding of Zn2+ to the closed K-A channels keeps the channel in the closed state and explains the ion's concentration-dependent slowing effect on the activation of K-A current. This in turn accounts for the inhibitory effect of Zn2+ on the K-A current elicited from hyperpolarized holding pote ntials. Because the molecular mechanisms underlying these gating changes ar e kinetic interactions between the binding-unbinding of Zn2+ and the intrin sic gating processes of the channel, the shift of the inactivation curve an d slowing of K-A channel activation are quantitatively correlated with ambi ent Zn2+ over a wide concentration range without "saturation"; i.e., The ef fects are already manifest in micromolar Zn2+, yet are not saturated even i n millimolar Zn2+. Because the physiological concentration of Zn2+ could va ry over a similarly wide range according to neural activities, Zn2+ may be a faithful physiological "fine tuner," controlling and controlled by neural activities through its effect on the K-A current.