The effects of external Zn+2 and other divalent cations on K channels in squid giant axons were studied. At low concentration (2 mM) Zn+2 slows opening kinetics without affecting closing kinetics. Higher concentrations (5-40 mM) progressively slow opening and speed channel closing to a lesser degree. In terms of "shifts," opening kinetics are strongly shifted to the right on the voltage axis, and off kinetics much less so. The shift of the conductance-voltage relation along the axis is intermediate. Zinc's kinetic effects show little sign of saturation at the highest concentration attainable. Zn does not alter the shape of the instantaneous current-voltage relation of open channels. Some other divalent cations have effects similar to Zn+2, Hg2+ being the most potent and Ca+2 the least. After treatment with Hg+2, which is irreversible, Zn+2 still slows opening kinetics, which suggests that each channel has at least two sites for divalent cation action. The results are not compatible with a simple theory of fixed, uniform surface charges. They suggest that external cations interact directly with a negatively charged element of the gating apparatus that moves inward from the membrane's outer surface during activation. Examination of normal kinetics shows that there is a slow step somewhere in the chain leading to channel opening. But the slowest step must not be the last one.

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