Abstract
Ether-à-go-go1 (Eag1, Kv10.1, KCNH1) K+ channel is a member of the voltage-gated K+ channel family mainly distributed in the central nervous system and cancer cells. Like other types of voltage-gated K+ channels, the EAG1 channels are regulated by a variety of endogenous signals including reactive oxygen species, rendering the EAG1 to be in the redox-regulated ion channel family. The role of EAG1 channels in tumor development and its therapeutic significance have been well established. Meanwhile, the importance of hEAG1 channels in the nervous system is now increasingly appreciated. The present review will focus on the recent progress on the channel regulation by endogenous signals and the potential functions of EAG1 channels in normal neuronal signaling as well as neurological diseases.
Highlights
Ether-a-go-go1 (Eag1), a voltage-gated K+ (Kv) channel firstly identified in a leg shaking mutant phenotype of Drosophila caused by spontaneously repetitive action potential firing in motor neurons and increased transmitter release [1, 2], is conserved in diverse mammalian species including human
Lacking more detailed information, our results suggested that, similar to the approach by which Ca2+/CaM inhibits EAG1 channels [45], PIP2 may alter the voltage dependence of activation by changing the physical coupling between eag domain and cyclic nucleotide binding homology domain (CNBHD) [14, 17]
Besides the plasma membrane, EAG1 channel has been reported to be present in the inner membrane of the nuclear, indicating the channel may play some unexpected roles in gene regulation
Summary
Ether-a-go-go (Eag1), a voltage-gated K+ (Kv) channel firstly identified in a leg shaking mutant phenotype of Drosophila caused by spontaneously repetitive action potential firing in motor neurons and increased transmitter release [1, 2], is conserved in diverse mammalian species including human. Two EAG isoforms Eag (KCNH1, Kv10.1) and Eag (KCNH5, Kv10.2) have been identified and they show similar electrophysiological features such as slow voltage-dependent activation, noninactivating, and inhibition by intracellular Ca2+ [Ca2+]i [4, 6, 7] Their responses to extracellular quinidine, a broad-spectrum K+ channel inhibitor, were noticeably different, indicating this compound can be used to distinguish the EAG channel subtypes in native cells [7]. Even though the overall architecture of the EAG1 channels is similar to that of previously crystallized Kv channel structures, there are many different aspects in S2-S3 linker, S4, and S4-S5 linker based on the structural models of rat EAG1 (rEAG1) channels derived by singleparticle cryoelectron microscopy (cryo-EM) [14] These local structural characters may determine that EAG1 channel has a fundamentally different voltage gating process compared to other types Kv channels. This article will briefly summarize the recent progress on the mechanisms of EAG1 channel gating regulation by endogenous molecules and discuss its physiological and pathological functions in nervous systems in mammals
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