NIP domain prevents N-type inactivation in voltage-gated potassium channels

Shaker -related voltage-gated K + (K v ) channels 1 , 2 are assembled from ion-conducting K v α subunits, which are integral membrane proteins, and auxiliary K v β subunits. This leads to the formation of highly diverse heteromultimeric K v channels that mediate outward currents with a wide range of time courses for inactivation. Two principal inactivation mechanisms have been recognized 1 : C-type inactivation correlated with carboxy-terminal K v α-subunit structures 3 , and N-type inactivation conferred by ‘ball’ domains in the amino termini of certain K v α 4 , 5 and K v β 6 subunits. Assembly of heteromultimers with one or more K v α 4 , 7 - and/or K v β 6 ball domains appears to be an essential principle of the generation of A-type K v channel diversity. Here we show that, unexpectedly, the presence of K v α- or K v β-ball domains does not dominate the gating phenotype in heteromultimers containing K v 1.6α subunits. These heteromultimers mediate non-inactivating currents because of the dominant-negative activity of a new type of N-type inactivation-prevention (NIP) domain present in the K v 1.6 amino terminus. Mutations in the NIP domain lead to loss of function, and its transfer to another K v α subunit leads to gain of function. Our discovery of the NIP domain, which neutralizes the activity of K v α- and K v β-inactivation gates, establishes a new determinant for the gating behaviour of heteromultimeric K v channels.