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

Shaker-related voltage-gated K+ (Kv) channels1,2 are assembled from ion-conducting Kvα subunits, which are integral membrane proteins, and auxiliary Kvβ subunits. This leads to the formation of highly diverse heteromultimeric Kv channels that mediate outward currents with a wide range of time courses for inactivation. Two principal inactivation mechanisms have been recognized1: C-type inactivation correlated with carboxy-terminal Kvα-subunit structures3, and N-type inactivation conferred by ‘ball’ domains in the amino termini of certain Kvα4,5 and Kvβ6 subunits. Assembly of heteromultimers with one or more Kvα4,7- and/or Kvβ6 ball domains appears to be an essential principle of the generation of A-type Kv channel diversity. Here we show that, unexpectedly, the presence of Kvα- or Kvβ-ball domains does not dominate the gating phenotype in heteromultimers containing Kv1.6α 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 Kv1.6 amino terminus. Mutations in the NIP domain lead to loss of function, and its transfer to another Kvα subunit leads to gain of function. Our discovery of the NIP domain, which neutralizes the activity of Kvα- and Kvβ-inactivation gates, establishes a new determinant for the gating behaviour of heteromultimeric Kv channels.