Role of the N-Terminal PAS Domain of hERG K Channels in Gating, Disease and Rescue

Abstract

Human ERG (Kv11 or KCNH2) channels are voltage-activated K channels in the eag family of channels. hERG is similar to other eag family member as they are homologous to voltage- activated K channels but also share homology with cyclic nucleotide-gated (CNG) channels. hERG shares important structural features with other members of the eag family including an N-terminal PAS domain (Per-Arnt-Sim) and C-terminal cyclic nucleotide-binding homology domain that is similar to the CNB domain of CNG, however eag family channels are not regulated by cyclic nucleotide. We have recently shown several new properties for the hERG PAS domain and CNBHD. Recently, we showed that the PAS domain made a direct interaction with the rest of the channel and markedly regulated slow deactivation, which is a characteristic of wild-type hERG. The CNBHD also plays a role in deactivation gating; it is necessary for regulation of deactivation as channels with the CNBHD deleted lost slow deactivation. Biochemical pull-down interactions and electrophysiology experiments suggest that the PAS domain makes a direct interaction with the CNBHD and that this interaction underlies slow deactivation. Mutations in hERG-PAS that are linked to LQTS disrupt the interaction of the PAS domain with the rest of the channel, indicating that disruption of this interaction may be the mechanism behind some instances of LQTS. The PAS domain itself can be used to fix aberrant gating in channels with PAS domain mutations, as if the recombinant PAS domain substitutes for the covalently attached, but mutated PAS domain. Here we will also discuss new data regarding the regulatory effect of the PAS domain on other gating transitions besides deactivation and the role of the region that connects the PAS domain to the transmembrane domain of the channel.