Inactivation of K+ channels responsible for delayed rectification in rat type II alveolar epithelial cells was studied in Ringer, 160 mM K-Ringer, and 20 mM Ca-Ringer. Inactivation is slower and less complete when the extracellular K+ concentration is increased from 4.5 to 160 mM. Inactivation is faster and more complete when the extracellular Ca2+ concentration is increased from 2 to 20 mM. Several observations suggest that inactivation is state-dependent. In each of these solutions depolarization to potentials near threshold results in slow and partial inactivation, whereas depolarization to potentials at which the K+ conductance, gK, is fully activated results in maximal inactivation, suggesting that open channels inactivate more readily than closed channels. The time constant of current inactivation during depolarizing pulses is clearly voltage-dependent only at potentials where activation is incomplete, a result consistent with coupling of inactivation to activation. Additional evidence for state-dependent inactivation includes cumulative inactivation and nonmonotonic from inactivation. A model like that proposed by C.M. Armstrong (1969. J. Gen. Physiol. 54: 553-575) for K+ channel block by internal quaternary ammonium ions accounts for most of these properties. The fundamental assumptions are: (a) inactivation is strictly coupled to activation (channels must open before inactivating, and recovery from inactivation requires passage through the open state); (b) the rate of inactivation is voltage-independent. Experimental data support this coupled model over models in which inactivation of closed channels is more rapid than that of open channels (e.g., Aldrich, R.W. 1981. Biophys. J. 36:519-532). No inactivation results from repeated depolarizing pulses that are too brief to open K+ channels. Inactivation is proportional to the total time that channels are open during both a depolarizing pulse and the tail current upon repolarization; repolarizing to more negative potentials at which the tail current decays faster results in less inactivation. Implications of the coupled model are discussed, as well as additional states needed to explain some details of inactivation kinetics.

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