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 alpha subunits, which are integral membrane protei ns, and auxiliary K-v beta subunits. This leads to the formation of hi ghly diverse heteromultimeric K-v channels that mediate outward curren ts with a wide range of time courses for inactivation, Two principal i nactivation mechanisms have been recognized(1): C-type inactivation co rrelated with carboxy-terminal K-v alpha-subunit structures(3), and N- type inactivation conferred by 'ball' domains in the amino termini of certain K-v alpha(4,5) and K-v beta(6) subunits, Assembly of heteromul timers with one or more K-v alpha(4,7)- and/or K-v beta(6) ball domain s 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 alpha- or K-v beta-ball domains does not dominate the gating phenot ype in heteromultimers containing K(v)1.6 alpha subunits. These hetero multimers mediate non-inactivating currents because of the dominant-ne gative 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 dom ain lead to loss of function, and its transfer to another K-v alpha su bunit leads to gain of function. Our discovery of the NIP domain, whic h neutralizes the activity of K-v alpha- and K-v beta-inactivation gat es, establishes a new determinant for the gating behaviour of heteromu ltimeric K-v channels.