XXXX receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism.

@entity72865 @entity1521 @entity72864 @entity4176 @entity4663 @entity4664 @entity19942 @entity2373
KEY POINTS: @entity4176 receptor heteromerization and auxiliary subunits, @entity72864 and @entity72865 , attenuate @entity4664 ion-channel block by facilitating blocker permeation. Relief of @entity4664 block in @entity2373 / @entity19942 heteromers results from a key @entity1521 residue that produces architectural changes in the channel pore a-helical region. Auxiliary subunits exert an additive effect to heteromerization, and thus relief of @entity4664 block is due to a different mechanism. Our findings have broad implications for work on @entity4664 block of other cation-selective ion channels. ABSTRACT: Channel block and permeation by cytoplasmic @entity4663 is a common feature of many cation-selective ion channels. Although the channel block mechanism has been studied extensively, @entity4664 permeation has been considered less significant as it occurs at extreme positive membrane potentials. Here, we show that @entity4176 receptor (KAR) heteromerization and association with auxiliary proteins, @entity72864 and @entity72865 , attenuate @entity4664 block by enhancing blocker permeation. Consequently, @entity4664 permeation and unblock occur at more negative and physiologically relevant membrane potentials. In @entity2373 / @entity19942 heteromers, enhanced permeation is due to a single @entity1521 residue in @entity19942 that alters the dynamics of the a-helical region of the selectivity filter. The effect of auxiliary proteins is additive, and therefore the structural basis of @entity4664 permeation and unblock is through a different mechanism. As native receptors are thought to assemble as heteromers in complex with auxiliary proteins, our data identify an unappreciated impact of @entity4664 permeation in shaping the signalling properties of neuronal KARs and point to a structural mechanism that may be shared amongst other cation-selective ion channels.
