A Distinct Potassium Channel Polypeptide Encoded by the
            <i>Drosophila eag</i>
            Locus

Warmke, Jeffrey W.; Drysdale, Rachel; Ganetzky, Barry

doi:10.1126/science.1840699

Cited by 330 publications

(218 citation statements)

References 39 publications

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“…The second interaction is the hydrogen bond between the hydroxyl groups of Tyr66 and Thr60 that further constrain the side-chain position of Tyr66. Of both interactions the hydrophobic packing of the aromatic ring appears to be more critical for the filter stability and channel selectivity, as the position equivalent to Tyr66 can also be Phe in some K þ channels (31,32). Indeed, replacing Tyr66 with Phe in NaK2K still yields a K þ selective channel (NaK2K_Y66F) with virtually the identical filter structure as NaK2K (Fig.…”

Section: Resultsmentioning

confidence: 98%

Protein interactions central to stabilizing the K ⁺ channel selectivity filter in a four-sited configuration for selective K ⁺ permeation

Sauer

Zeng

Raghunathan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The structural and functional conversion of the nonselective NaK channel to a K + selective channel (NaK2K) allows us to identify two key residues, Tyr and Asp in the filter sequence of TVG Y G D , that participate in interactions central to stabilizing the K + channel selectivity filter. By using protein crystallography and channel electrophysiology, we demonstrate that the K + channel filter exists as an energetically strained structure and requires these key protein interactions working in concert to hold the filter in the precisely defined four-sited configuration that is essential for selective K + permeation. Disruption of either interaction, as tested on both the NaK2K and eukaryotic K v 1.6 channels, can reduce or completely abolish K + selectivity and in some cases may also lead to channel inactivation due to conformational changes at the filter. Additionally, on the scaffold of NaK we recapitulate the protein interactions found in the filter of the Kir channel family, which uses a distinct interaction network to achieve similar stabilization of the filter.

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Section: Resultsmentioning

confidence: 98%

Protein interactions central to stabilizing the K ⁺ channel selectivity filter in a four-sited configuration for selective K ⁺ permeation

Sauer

Zeng

Raghunathan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Ether à go-go (Eag) potassium channels were first detected in Drosophila melanogaster (1)(2)(3). In vertebrates, the Eag family is formed by eight members distributed in three subfamilies (e.g.…”

mentioning

confidence: 99%

Silencing the Activity and Proliferative Properties of the Human EagI Potassium Channel by RNA Interference

Weber

Queiroz

Downie

et al. 2006

Journal of Biological Chemistry

115

118

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EagI potassium channels are natively expressed in the mammalian brain as well as in many cancer cell lines and tumor tissues. The role of EagI in malignant transformation has been suggested by several experiments, but the lack of specific EagI inhibitors has made it difficult to examine the influence of the channel on oncogenesis and its potential as a therapeutic target. We have used short interfering RNA to test the effects of EagI reduction on the behavior of tumor cells in vitro. By generating and optimizing an EagI-specific short interfering RNA system, we were able to study the effects of EagI depletion on several cancer cell lines that endogenously express this protein. We show here that our short interfering RNA sequences act specifically on EagI, reproducibly induce a significant decrease in the proliferation of tumor cell lines, and do not trigger any observable nonspecific responses.

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“…activation ͉ voltage-gated D rosophila ether-à-go-go (eag) is the original member of a subfamily of voltage-dependent K ϩ channels that includes eag, eag-related gene (erg), and eag-like (elk) channels (1,2). In mammals, these channels are expressed in the brain and heart, where they play key roles in controlling excitability (2)(3)(4).…”

mentioning

confidence: 99%

Optical detection of rate-determining ion-modulated conformational changes of the ether-à-go-go K ⁺ channel voltage sensor

Bannister

Chanda

Bezanilla

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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In voltage-dependent ether-à -go-go (eag) K ؉ channels, the process of activation is modulated by Mg 2؉ and other divalent cations, which bind to a site in the voltage sensor and slow channel opening. Previous analysis of eag ionic and gating currents indicated that Mg 2؉ has a much larger effect on ionic than gating current kinetics. From this, we hypothesized that ion binding modulates voltage sensor conformational changes that are poorly represented in gating current recordings. We have now tested this proposal by using a combined electrophysiological and optical approach. We find that a fluorescent probe attached near S4 in the voltage sensor reports on two phases of the activation process. One component of the optical signal corresponds to the main charge-moving conformational changes of the voltage sensor. This is the phase of activation that is well represented in gating current recordings. Another component of the optical signal reflects voltage sensor conformational changes that occur at more hyperpolarized potentials. These transitions, which are rate-determining for activation and highly modulated by Mg 2؉ , have not been detected in gating current recordings. Our results demonstrate that the eag voltage sensor undergoes conformational changes that have gone undetected in electrical measurements. These transitions account for the time course of eag activation in the presence and absence of extracellular Mg 2؉ .activation ͉ voltage-gated D rosophila ether-à-go-go (eag) is the original member of a subfamily of voltage-dependent K ϩ channels that includes eag, eag-related gene (erg), and eag-like (elk) channels (1, 2). In mammals, these channels are expressed in the brain and heart, where they play key roles in controlling excitability (2-4). For example, human erg (HERG) channels contribute significantly to the repolarization of the cardiac action potential (3). Disruption of HERG activity results in long QT syndrome, a predisposition to cardiac arrhythmia and sudden death (3,5,6).Eag channels comprise four subunits surrounding a central pore for K ϩ permeation (7). Each subunit has six transmembrane segments. The last two transmembrane segments (S5 and S6) and the intervening P loop form the ion selective pore, whereas S1-S4 form the voltage sensor (8, 9). Voltage control of channel activity is primarily due to the S4 segment, which contains multiple positively charged residues (10). In response to changes in transmembrane voltage, charged residues in S4 initiate conformational changes that control whether the pore is open or closed (11, 12). S4 conformational changes can be measured electrically as gating currents (13).Channels in the eag subfamily are subject to a novel form of regulation by extracellular divalent cations (14-16). In eag channels, the process of voltage-dependent activation is modulated directly by binding of divalent cations to a site in the voltage sensor (16,17). Extracellular divalent ions, including Mg 2ϩ , Mn 2ϩ , and Ni 2ϩ , slow activation kinetics (14, 18). The halfmaximal e...

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A Distinct Potassium Channel Polypeptide Encoded by the Drosophila eag Locus

Cited by 330 publications

References 39 publications

Protein interactions central to stabilizing the K ⁺ channel selectivity filter in a four-sited configuration for selective K ⁺ permeation

Protein interactions central to stabilizing the K ⁺ channel selectivity filter in a four-sited configuration for selective K ⁺ permeation

Silencing the Activity and Proliferative Properties of the Human EagI Potassium Channel by RNA Interference

Optical detection of rate-determining ion-modulated conformational changes of the ether-à-go-go K ⁺ channel voltage sensor

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A Distinct Potassium Channel Polypeptide Encoded by the Drosophila eag Locus

Cited by 330 publications

References 39 publications

Protein interactions central to stabilizing the K + channel selectivity filter in a four-sited configuration for selective K + permeation

Protein interactions central to stabilizing the K + channel selectivity filter in a four-sited configuration for selective K + permeation

Silencing the Activity and Proliferative Properties of the Human EagI Potassium Channel by RNA Interference

Optical detection of rate-determining ion-modulated conformational changes of the ether-à-go-go K + channel voltage sensor

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Resources

About

Protein interactions central to stabilizing the K ⁺ channel selectivity filter in a four-sited configuration for selective K ⁺ permeation

Protein interactions central to stabilizing the K ⁺ channel selectivity filter in a four-sited configuration for selective K ⁺ permeation

Optical detection of rate-determining ion-modulated conformational changes of the ether-à-go-go K ⁺ channel voltage sensor