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) current) by Zn(2+) was studied in rat hippocampal neurons by the whole-cell patch-clamp technique. It is found that Zn(2+) selectively binds to the resting (deactivated or closed) K(A) channels with a dissociation constant (K(d)) of approximately 3 microM, whereas the affinity between Zn(2+) and the inactivated K(A) channels is 1000-fold lower. Zn(2+) therefore produces a concentration-dependent shift of the K(A) channel inactivation curve and enhances the K(A) current elicited from relatively positive holding potentials. It is also found that the kinetics of Zn(2+) action are fast enough to compete with the transition rates between different gating states of the channel. The rapid and selective binding of Zn(2+) 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 Zn(2+) on the K(A) current elicited from hyperpolarized holding potentials. Because the molecular mechanisms underlying these gating changes are kinetic interactions between the binding-unbinding of Zn(2+) and the intrinsic gating processes of the channel, the shift of the inactivation curve and slowing of K(A) channel activation are quantitatively correlated with ambient Zn(2+) over a wide concentration range without "saturation"; i.e., The effects are already manifest in micromolar Zn(2+), yet are not saturated even in millimolar Zn(2+). Because the physiological concentration of Zn(2+) could vary over a similarly wide range according to neural activities, Zn(2+) may be a faithful physiological "fine tuner," controlling and controlled by neural activities through its effect on the K(A) current.
Kuo
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CC
Department of Physiology, National Taiwan University College of Medicine, National Taiwan University Hospital, Taipei 100, Taiwan, Republic of China. cckuo@ha.mc.ntu.edu.tw
Chen
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FP
D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D013379:Substrate Specificity; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology*
D024642:Potassium Channels, Voltage-Gated; D002104:Cadmium; D015032:Zinc; D011188:Potassium