NIP domain prevents N-type inactivation in voltage-gated potassium channels
NIP domain prevents N-type inactivation in voltage-gated potassium channels
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作者：
Roeper, J;Sewing, S;Pongs, O
振动器相关的电压门控K+ (K-v)通道（1,2）由离子传导的K-v α亚基（完整的膜蛋白）和辅助的K-v β亚基组装而成。这导致形成高度多样化的异质K-v通道，介导具有大范围失活时间的向外电流。已经确认了两种主要失活机制(1)：c型失活与羧基端K-v α亚基结构相关(3)，n型失活与某些K-v α(4,5)和K-v β(6)亚基的氨基端“球”结构域有关。异构体与一个或多个K-v α(4,7)和/或K-v β(6)球结构域的组装似乎是a型K-v通道多样性产生的基本原理。在含有K(v)1.6 α亚基的异聚体中，K-v α -或K-v β -球结构域的存在并不主导门控表型。这些异多聚体介导非失活电流，因为K(v)1.6氨基端存在一种新型n型失活预防（NIP）结构域的显性负活性。NIP结构域的突变导致功能丧失，其转移到另一个K-v α亚基导致功能获得。我们发现的NIP结构域可以中和K-v α和K-v β失活门的活性，为异质K-v通道的门控行为建立了一个新的决定因素。
Shaker-related voltage-gated K+ (K-v) channels(1,2) are assembled from ion-conducting K-v alpha subunits, which are integral membrane proteins, and auxiliary K-v beta 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 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 heteromultimers with one or more K-v alpha(4,7)- and/or K-v beta(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 alpha- or K-v beta-ball domains does not dominate the gating phenotype in heteromultimers containing K(v)1.6 alpha 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 alpha subunit leads to gain of function. Our discovery of the NIP domain, which neutralizes the activity of K-v alpha- and K-v beta-inactivation gates, establishes a new determinant for the gating behaviour of heteromultimeric K-v channels.