Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy

Zhang, Xiaofei; Bertaso, Federica; Yoo, Jong W.; Baumgärtel, Karsten; Clancy, Sinead M.; Lee, Van; Cienfuegos, Cynthia; Wilmot, Carly; Avis, Jacqueline; Hunyh, Truc; Daguia, Catherine; Schmedt, Christian; Noebels, Jeffrey L.; Jegla, Timothy

doi:10.1038/nn.2610

Cited by 66 publications

(93 citation statements)

References 15 publications

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“…NvErg1 has both an I Kr -like phenotype and a hyperpolarized activation threshold, suggesting it could play roles in both plateau repolarization and subthreshold excitation, whereas NvErg4 may specifically regulate subthreshold behavior. The mammalian channel Elk2, like NvErg1, has an I Kr -like phenotype and low activation threshold that regulates subthreshold excitability in hippocampal pyramidal neurons (44). MmErg3 also has a relatively low activation threshold and is expressed primarily in neurons.…”

Section: Discussionmentioning

confidence: 99%

Functional evolution of Erg potassium channel gating reveals an ancient origin for I _Kr

Martinson

Rossum

Diatta

et al. 2014

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

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Mammalian Ether-a-go-go related gene (Erg) family voltage-gated K + channels possess an unusual gating phenotype that specializes them for a role in delayed repolarization. Mammalian Erg currents rectify during depolarization due to rapid, voltage-dependent inactivation, but rebound during repolarization due to a combination of rapid recovery from inactivation and slow deactivation. This is exemplified by the mammalian Erg1 channel, which is responsible for I Kr , a current that repolarizes cardiac action potential plateaus. The Drosophila Erg channel does not inactivate and closes rapidly upon repolarization. The dramatically different properties observed in mammalian and Drosophila Erg homologs bring into question the evolutionary origins of distinct Erg K + channel functions. Erg channels are highly conserved in eumetazoans and first evolved in a common ancestor of the placozoans, cnidarians, and bilaterians. To address the ancestral function of Erg channels, we identified and characterized Erg channel paralogs in the sea anemone Nematostella vectensis. N. vectensis Erg1 (NvErg1) is highly conserved with respect to bilaterian homologs and shares the I Kr -like gating phenotype with mammalian Erg channels. Thus, the I Kr phenotype predates the divergence of cnidarians and bilaterians. NvErg4 and Caenorhabditis elegans Erg (unc-103) share the divergent Drosophila Erg gating phenotype. Phylogenetic and sequence analysis surprisingly indicates that this alternate gating phenotype arose independently in protosomes and cnidarians. Conversion from an ancestral I Kr -like gating phenotype to a Drosophila Erg-like phenotype correlates with loss of the cytoplasmic Ether-a-go-go domain. This domain is required for slow deactivation in mammalian Erg1 channels, and thus its loss may partially explain the change in gating phenotype.sei | CNBHD | Anopheles | PAS

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Section: Discussionmentioning

confidence: 99%

Functional evolution of Erg potassium channel gating reveals an ancient origin for I _Kr

Martinson

Rossum

Diatta

et al. 2014

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

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“…The alignment between Kv10.2 and other Kv channels was generated with ClustalW2 and manually refined based on previous studies (Long et al, 2007;Pathak et al, 2007;Zhang et al, 2009 (Jensen et al, 2012). Modeling of the S1-S4 VSD in six states was performed with SWISS-MODEL (Arnold et al, 2006;Bordoli et al, 2009) and refined as described previously (Yang et al, , 2013.…”

Section: Methodsmentioning

confidence: 99%

“…These results indicate that R327H mutation makes the channel easy to open and produces a gain-of-function phenotype of the Kv10.2 channel, consistent with the multistate structural modeling results. It has been reported previously that extracellularly applied Mg 2ϩ slows activation kinetics and depolarizes steady-state activation of EAG channels through binding to the residues at the outer VSD (Terlau et al, 1996;Silverman et al, 2000Silverman et al, , 2004Schonherr et al, 2002;Zhang et al, 2009). Therefore, it could be possible that the hyperpolarizing shift seen in R327H mutation might partially arise from interference with the Mg 2ϩ effects on channel activation via the structural changes caused by this mutation.…”

Section: Voltage-clamp Analysismentioning

confidence: 98%

Multistate Structural Modeling and Voltage-Clamp Analysis of Epilepsy/Autism Mutation Kv10.2–R327H Demonstrate the Role of This Residue in Stabilizing the Channel Closed State

et al. 2013

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Voltage-gated potassium channel Kv10.2 (KCNH5) is expressed in the nervous system, but its functions and involvement in human disease are poorly understood. We studied a human Kv10.2 channel mutation (R327H) recently identified in a child with epileptic encephalopathy and autistic features. Using multistate structural modeling, we demonstrate that the Arg327 residue in the S4 helix of voltage-sensing domain has strong ionic interactions with negatively charged residues within the S1-S3 helices in the resting (closed) and early-activation state but not in the late-activation and fully-activated (open) state. The R327H mutation weakens ionic interactions between residue 327 and these negatively charged residues, thus favoring channel opening. Voltage-clamp analysis showed a strong hyperpolarizing (ϳ70 mV) shift of voltage dependence of activation and an acceleration of activation. Our results demonstrate the critical role of the Arg327 residue in stabilizing the channel closed state and explicate for the first time the structural and functional change of a Kv10.2 channel mutation associated with neurological disease.

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“…In Kenyon cells, which are central unipolar neurons responsible for higher order processing, GFP-tagged elk and shal K + channels concentrate in an AIS-like domain (Trunova et al, 2011). Elk channels regulate action potential threshold in vertebrate neurons (Zhang et al, 2010), while shal channels encode transient Acurrents, which influence both threshold and frequency (Jerng et al, 2004). These studies at a minimum suggest that the initial segment of Drosophila axons can serve as a boundary for ion channel distribution, and suggest that there may be a mechanism for clustering ion channels there.…”

Section: Reviewmentioning

confidence: 99%

Neuronal polarity: an evolutionary perspective

Rolls

Jegla

2015

Journal of Experimental Biology

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Polarized distribution of signaling molecules to axons and dendrites facilitates directional information flow in complex vertebrate nervous systems. The topic we address here is when the key aspects of neuronal polarity evolved. All neurons have a central cell body with thin processes that extend from it to cover long distances, and they also all rely on voltage-gated ion channels to propagate signals along their length. The most familiar neurons, those in vertebrates, have additional cellular features that allow them to send directional signals efficiently. In these neurons, dendrites typically receive signals and axons send signals. It has been suggested that many of the distinct features of axons and dendrites, including the axon initial segment, are found only in vertebrates. However, it is now becoming clear that two key cytoskeletal features that underlie polarized sorting, a specialized region at the base of the axon and polarized microtubules, are found in invertebrate neurons as well. It thus seems likely that all bilaterians generate axons and dendrites in the same way. As a next step, it will be extremely interesting to determine whether the nerve nets of cnidarians and ctenophores also contain polarized neurons with true axons and dendrites, or whether polarity evolved in concert with the more centralized nervous systems found in bilaterians. KEY WORDS: Axon, Dendrite, Axon initial segment, MicrotubuleIntroduction: are vertebrates special because of their neurons?The elaborate behaviors of vertebrates are made possible by the evolution of nervous systems of unparalleled size and complexity. The developmental mechanisms that assemble the vertebrate nervous system and physical mapping of the circuits that underlie behavior are subjects of intense study. But are the neurons of the vertebrate nervous system themselves also unique or special in some way? Do they have vertebrate-only features that facilitate the assembly of large, complex nervous systems? Or is the vertebrate nervous system based on an ancient and highly adaptable neuronal cell type? Understanding the evolutionary history of neurons is critical to understanding how vertebrate nervous systems and behavior came to be. Another very practical reason for asking these questions is that it is helpful to know which features of neurons are shared with and can thus be studied in cheap, efficient invertebrate model systems. Vertebrate-specific neuronal features, in contrast, must be studied in model systems such as zebrafish or mouse, for which time and expense often limit the scientific questions that can be asked.The polarized functional organization of neurons that facilitates assembly of complex circuits might be a good candidate for being associated specifically with vertebrates. Indeed, in a highly cited review on neuronal polarity from 1994, invertebrate neurons are seen as 'sufficiently different' in terms of organization from vertebrate neurons that the polarized sorting mechanisms are suggested to also differ (Craig and Banker, 1994...

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Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy

Cited by 66 publications

References 15 publications

Functional evolution of Erg potassium channel gating reveals an ancient origin for I _Kr

Functional evolution of Erg potassium channel gating reveals an ancient origin for I _Kr

Multistate Structural Modeling and Voltage-Clamp Analysis of Epilepsy/Autism Mutation Kv10.2–R327H Demonstrate the Role of This Residue in Stabilizing the Channel Closed State

Neuronal polarity: an evolutionary perspective

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Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy

Cited by 66 publications

References 15 publications

Functional evolution of Erg potassium channel gating reveals an ancient origin for I Kr

Functional evolution of Erg potassium channel gating reveals an ancient origin for I Kr

Multistate Structural Modeling and Voltage-Clamp Analysis of Epilepsy/Autism Mutation Kv10.2–R327H Demonstrate the Role of This Residue in Stabilizing the Channel Closed State

Neuronal polarity: an evolutionary perspective

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Functional evolution of Erg potassium channel gating reveals an ancient origin for I _Kr

Functional evolution of Erg potassium channel gating reveals an ancient origin for I _Kr