1.A.1.20.4
K⁺ voltage-gated channel, rEAG1; K_v10.1; rat ether a go-go channel 1 (962 aas). Blocked by Cs⁺, Ba²⁺ and quinidine (Schwarzer et al., 2008). Cysteines control the N- and C-linker-dependent gating of KCNH1 potassium channels  (Sahoo et al., 2012).  The 3-d structure has been determined at 3.8 Å resolution using single-particle cryo-EM with calmodulin bound. The structure suggests a novel mechanism of voltage-dependent gating. Calmodulin binding closes the potassium pore (Whicher and MacKinnon 2016). Eag1 has three intracellular domains: PAS, C-linker, and CNBHD. Whicher and MacKinnon 2019 demonstrated that the Eag1 intracellular domains are not required for voltage-dependent gating but likely interact with the VS to modulate gating. Specific interactions between the PAS, CNBHD, and VS domains modulate voltage-dependent gating, and VS movement destabilizes these interactions to promote channel opening. Mutations affecting these interactions render Eag1 insensitive to calmodulin inhibition (Whicher and MacKinnon 2019). The structure of the calmodulin insensitive mutant in a pre-open conformation suggests that channel opening may occur through a rotation of the intracellular domains, and calmodulin may prevent this rotation by stabilizing interactions between the VS and the other intracellular domains. Intracellular domains likely play a similar modulatory role in voltage-dependent gating of the related Kv11-12 channels. The human ortholog, EAG or EAG-1, is 989 aas long and is 95% identical to the rat protein.  In ether-a-go-go K⁺ channels, voltage-dependent activation is modulated by ion binding to a site located in an extracellular-facing crevice between transmembrane segments S2 and S3 in the voltage sensor. Silverman et al. 2004 found that acidic residues, D278 in S2 and D327 in S3, are able to coordinate a variety of divalent cations, including Mg²⁺, Mn²⁺, and Ni²⁺, which have qualitatively similar functional effects, but different half-maximal effective concentrations. EAG (ether-a-go-go) voltage-dependent K⁺ channels with similarities and Differences in the structural organization and gating (Barros et al. 2020).

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