MODULATION OF K- A TALE OF 2 INACTIVATION MECHANISMS( CURRENT BY FREQUENCY AND EXTERNAL [K+] )

Voltage-activated K+ currents and their inactivation properties are im portant for controlling frequency-dependent signaling in neurons and o ther excitable cells. Two distinct molecular mechanisms for K+ channel inactivation have been described: N-type, which involves rapid occlus ion of the open channel by an intracellular tethered blocker, and C-ty pe, which involves a slower change at the extracellular mouth of the p ore. We find that frequency-dependent cumulative inactivation of Shake r channels is very sensitive to changes of extracellular [K+] in the p hysiological range, with much more inactivation at low [K+](out), and that it results from the interaction of N- and C-type inactivation. N- type inactivation enhances C-type inactivation by two mechanisms. Firs t, it inhibits outward K+ flux, which normally fills an external ion s ite and thus prevents C-type inactivation. Second, it keeps the channe l's activation gate open even after repolarization, allowing C-type in activation to occur for a prolonged period.