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  1. Book: Kcnq2- And Kcnq3-Associated Epilepsy

    Weckhuysen, Sarah / George Jr, Alfred L

    2022  

    Language English
    Size 75 p.
    Publisher CAMBRIDGE
    Document type Book
    Note PDA Manuell_18
    Format 152 x 229 x 6
    ISBN 9781009278263 ; 1009278266
    Database PDA

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  2. Article ; Online: Scanning mutagenesis of the voltage-gated sodium channel NaV1.2 using base editing

    Juan Lorenzo B. Pablo / Savannah L. Cornett / Lei A. Wang / Sooyeon Jo / Tobias Brünger / Nikita Budnik / Mudra Hegde / Jean-Marc DeKeyser / Christopher H. Thompson / John G. Doench / Dennis Lal / Alfred L. George, Jr. / Jen Q. Pan

    Cell Reports, Vol 42, Iss 6, Pp 112563- (2023)

    2023  

    Abstract: Summary: It is challenging to apply traditional mutational scanning to voltage-gated sodium channels (NaVs) and functionally annotate the large number of coding variants in these genes. Using a cytosine base editor and a pooled viability assay, we screen ...

    Abstract Summary: It is challenging to apply traditional mutational scanning to voltage-gated sodium channels (NaVs) and functionally annotate the large number of coding variants in these genes. Using a cytosine base editor and a pooled viability assay, we screen a library of 368 guide RNAs (gRNAs) tiling NaV1.2 to identify more than 100 gRNAs that change NaV1.2 function. We sequence base edits made by a subset of these gRNAs to confirm specific variants that drive changes in channel function. Electrophysiological characterization of these channel variants validates the screen results and provides functional mechanisms of channel perturbation. Most of the changes caused by these gRNAs are classifiable as loss of function along with two missense mutations that lead to gain of function in NaV1.2 channels. This two-tiered strategy to functionally characterize ion channel protein variants at scale identifies a large set of loss-of-function mutations in NaV1.2.
    Keywords CP: Neuroscience ; Biology (General) ; QH301-705.5
    Subject code 003
    Language English
    Publishing date 2023-06-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Cholesterol-induced suppression of Kir2 channels is mediated by decoupling at the inter-subunit interfaces

    Nicolas Barbera / Sara T. Granados / Carlos Guillermo Vanoye / Tatiana V. Abramova / Danielle Kulbak / Sang Joon Ahn / Alfred L. George, Jr. / Belinda S. Akpa / Irena Levitan

    iScience, Vol 25, Iss 5, Pp 104329- (2022)

    2022  

    Abstract: Summary: Cholesterol is a major regulator of multiple types of ion channels. Although there is increasing information about cholesterol binding sites, the molecular mechanisms through which cholesterol binding alters channel function are virtually ... ...

    Abstract Summary: Cholesterol is a major regulator of multiple types of ion channels. Although there is increasing information about cholesterol binding sites, the molecular mechanisms through which cholesterol binding alters channel function are virtually unknown. In this study, we used a combination of Martini coarse-grained simulations, a network theory-based analysis, and electrophysiology to determine the effect of cholesterol on the dynamic structure of the Kir2.2 channel. We found that increasing membrane cholesterol reduced the likelihood of contact between specific regions of the cytoplasmic and transmembrane domains of the channel, most prominently at the subunit-subunit interfaces of the cytosolic domains. This decrease in contact was mediated by pairwise interactions of specific residues and correlated to the stoichiometry of cholesterol binding events. The predictions of the model were tested by site-directed mutagenesis of two identified residues—V265 and H222—and high throughput electrophysiology.
    Keywords Cellular physiology ; Molecular biology ; Biophysics ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: High-throughput evaluation of epilepsy-associated KCNQ2 variants reveals functional and pharmacological heterogeneity

    Carlos G. Vanoye / Reshma R. Desai / Zhigang Ji / Sneha Adusumilli / Nirvani Jairam / Nora Ghabra / Nishtha Joshi / Eryn Fitch / Katherine L. Helbig / Dianalee McKnight / Amanda S. Lindy / Fanggeng Zou / Ingo Helbig / Edward C. Cooper / Alfred L. George Jr.

    JCI Insight, Vol 7, Iss

    2022  Volume 5

    Abstract: Hundreds of genetic variants in KCNQ2 encoding the voltage-gated potassium channel KV7.2 are associated with early onset epilepsy and/or developmental disability, but the functional consequences of most variants are unknown. Absent functional annotation ... ...

    Abstract Hundreds of genetic variants in KCNQ2 encoding the voltage-gated potassium channel KV7.2 are associated with early onset epilepsy and/or developmental disability, but the functional consequences of most variants are unknown. Absent functional annotation for KCNQ2 variants hinders identification of individuals who may benefit from emerging precision therapies. We employed automated patch clamp recordings to assess at, to our knowledge, an unprecedented scale the functional and pharmacological properties of 79 missense and 2 inframe deletion KCNQ2 variants. Among the variants we studied were 18 known pathogenic variants, 24 mostly rare population variants, and 39 disease-associated variants with unclear functional effects. We analyzed electrophysiological data recorded from 9,480 cells. The functional properties of 18 known pathogenic variants largely matched previously published results and validated automated patch clamp for this purpose. Unlike rare population variants, most disease-associated KCNQ2 variants exhibited prominent loss-of-function with dominant-negative effects, providing strong evidence in support of pathogenicity. All variants responded to retigabine, although there were substantial differences in maximal responses. Our study demonstrated that dominant-negative loss-of-function is a common mechanism associated with missense KCNQ2 variants. Importantly, we observed genotype-dependent differences in the response of KCNQ2 variants to retigabine, a proposed precision therapy for KCNQ2 developmental and epileptic encephalopathy.
    Keywords Genetics ; Neuroscience ; Medicine ; R
    Subject code 616
    Language English
    Publishing date 2022-03-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation

    Georg Kuenze / Carlos G Vanoye / Reshma R Desai / Sneha Adusumilli / Kathryn R Brewer / Hope Woods / Eli F McDonald / Charles R Sanders / Alfred L George Jr / Jens Meiler

    eLife, Vol

    2020  Volume 9

    Abstract: The function of the voltage-gated KCNQ1 potassium channel is regulated by co-assembly with KCNE auxiliary subunits. KCNQ1-KCNE1 channels generate the slow delayed rectifier current, IKs, which contributes to the repolarization phase of the cardiac action ...

    Abstract The function of the voltage-gated KCNQ1 potassium channel is regulated by co-assembly with KCNE auxiliary subunits. KCNQ1-KCNE1 channels generate the slow delayed rectifier current, IKs, which contributes to the repolarization phase of the cardiac action potential. A three amino acid motif (F57-T58-L59, FTL) in KCNE1 is essential for slow activation of KCNQ1-KCNE1 channels. However, how this motif interacts with KCNQ1 to control its function is unknown. Combining computational modeling with electrophysiological studies, we developed structural models of the KCNQ1-KCNE1 complex that suggest how KCNE1 controls KCNQ1 activation. The FTL motif binds at a cleft between the voltage-sensing and pore domains and appears to affect the channel gate by an allosteric mechanism. Comparison with the KCNQ1-KCNE3 channel structure suggests a common transmembrane-binding mode for different KCNEs and illuminates how specific differences in the interaction of their triplet motifs determine the profound differences in KCNQ1 functional modulation by KCNE1 versus KCNE3.
    Keywords KCNQ1 ; KCNE1 ; long QT syndrome ; voltage-gated potassium ion channel ; Rosetta ; molecular dynamics simulation ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Impact of CYP2C9‐Interacting Drugs on Warfarin Pharmacogenomics

    Saaket Agrawal / Meredith S. Heiss / Remington B. Fenter / Tatiana V. Abramova / Minoli A. Perera / Jennifer A. Pacheco / Maureen E. Smith / Laura J. Rasmussen‐Torvik / Alfred L. George Jr.

    Clinical and Translational Science, Vol 13, Iss 5, Pp 941-

    2020  Volume 949

    Abstract: Precise dosing of warfarin is important to achieve therapeutic benefit without adverse effects. Pharmacogenomics explains some interindividual variability in warfarin response, but less attention has been paid to drug‐drug interactions in the context of ... ...

    Abstract Precise dosing of warfarin is important to achieve therapeutic benefit without adverse effects. Pharmacogenomics explains some interindividual variability in warfarin response, but less attention has been paid to drug‐drug interactions in the context of genetic factors. We investigated retrospectively the combined effects of cytochrome P450 (CYP)2C9 and vitamin K epoxide reductase complex (VKORC)1 genotypes and concurrent exposure to CYP2C9‐interacting drugs on long‐term measures of warfarin anticoagulation. Study participants predicted to be sensitive responders to warfarin based on CYP2C9 and VKORC1 genotypes, had significantly greater international normalized ratio (INR) variability over time. Participants who were concurrently taking CYP2C9‐interacting drugs were found to have greater INR variability and lesser time in therapeutic range. The associations of INR variability with genotype were driven by the subgroup not exposed to interacting drugs, whereas the effect of interacting drug exposure was driven by the subgroup categorized as normal responders. Our findings emphasize the importance of considering drug interactions in pharmacogenomic studies.
    Keywords Therapeutics. Pharmacology ; RM1-950 ; Public aspects of medicine ; RA1-1270
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Dyshomeostatic modulation of Ca2+-activated K+ channels in a human neuronal model of KCNQ2 encephalopathy

    Dina Simkin / Kelly A Marshall / Carlos G Vanoye / Reshma R Desai / Bernabe I Bustos / Brandon N Piyevsky / Juan A Ortega / Marc Forrest / Gabriella L Robertson / Peter Penzes / Linda C Laux / Steven J Lubbe / John J Millichap / Alfred L George Jr / Evangelos Kiskinis

    eLife, Vol

    2021  Volume 10

    Abstract: Mutations in KCNQ2, which encodes a pore-forming K+ channel subunit responsible for neuronal M-current, cause neonatal epileptic encephalopathy, a complex disorder presenting with severe early-onset seizures and impaired neurodevelopment. The condition ... ...

    Abstract Mutations in KCNQ2, which encodes a pore-forming K+ channel subunit responsible for neuronal M-current, cause neonatal epileptic encephalopathy, a complex disorder presenting with severe early-onset seizures and impaired neurodevelopment. The condition is exceptionally difficult to treat, partially because the effects of KCNQ2 mutations on the development and function of human neurons are unknown. Here, we used induced pluripotent stem cells (iPSCs) and gene editing to establish a disease model and measured the functional properties of differentiated excitatory neurons. We find that patient iPSC-derived neurons exhibit faster action potential repolarization, larger post-burst afterhyperpolarization and a functional enhancement of Ca2+-activated K+ channels. These properties, which can be recapitulated by chronic inhibition of M-current in control neurons, facilitate a burst-suppression firing pattern that is reminiscent of the interictal electroencephalography pattern in patients. Our findings suggest that dyshomeostatic mechanisms compound KCNQ2 loss-of-function leading to alterations in the neurodevelopmental trajectory of patient iPSC-derived neurons.
    Keywords KCNQ2 ; epileptic encephalopathy ; M-current ; dyshomeostatic ; homeostatic plasticity ; disease modeling ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article: KCNE4 can co-associate with the IKs (KCNQ1-KCNE1) channel complex

    Manderfield, Lauren J / George, Alfred L. Jr

    FEBS journal. 2008 Mar., v. 275, no. 6

    2008  

    Abstract: Voltage-gated potassium (KV) channels can form heteromultimeric complexes with a variety of accessory subunits, including KCNE proteins. Heterologous expression studies have demonstrated diverse functional effects of KCNE subunits on several KV channels, ...

    Abstract Voltage-gated potassium (KV) channels can form heteromultimeric complexes with a variety of accessory subunits, including KCNE proteins. Heterologous expression studies have demonstrated diverse functional effects of KCNE subunits on several KV channels, including KCNQ1 (KV7.1) that, together with KCNE1, generates the slow-delayed rectifier current (IKs) important for cardiac repolarization. In particular, KCNE4 exerts a strong inhibitory effect on KCNQ1 and other KV channels, raising the possibility that this accessory subunit is an important potassium current modulator. A polyclonal KCNE4 antibody was developed to determine the human tissue expression pattern and to investigate the biochemical associations of this protein with KCNQ1. We found that KCNE4 is widely and variably expressed in several human tissues, with greatest abundance in brain, liver and testis. In heterologous expression experiments, immunoprecipitation followed by immunoblotting was used to establish that KCNE4 directly associates with KCNQ1, and can co-associate together with KCNE1 in the same KCNQ1 complex to form a 'triple subunit' complex (KCNE1-KCNQ1-KCNE4). We also used cell surface biotinylation to demonstrate that KCNE4 does not impair plasma membrane expression of either KCNQ1 or the triple subunit complex, indicating that biophysical mechanisms probably underlie the inhibitory effects of KCNE4. The observation that multiple KCNE proteins can co-associate with and modulate KCNQ1 channels to produce biochemically diverse channel complexes has important implications for understanding KV channel regulation in human physiology.
    Language English
    Dates of publication 2008-03
    Size p. 1336-1349.
    Publisher Blackwell Publishing Ltd
    Publishing place Oxford, UK
    Document type Article
    ZDB-ID 2173655-8
    ISSN 1742-4658 ; 1742-464X
    ISSN (online) 1742-4658
    ISSN 1742-464X
    DOI 10.1111/j.1742-4658.2008.06294.x
    Database NAL-Catalogue (AGRICOLA)

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  9. Article: KCNE4 Juxtamembrane Region Is Required for Interaction with Calmodulin and for Functional Suppression of KCNQ1

    Ciampa, Erin J / Welch, Richard C / Vanoye, Carlos G / George, Alfred L. Jr

    Journal of biological chemistry. 2011 Feb. 11, v. 286, no. 6

    2011  

    Abstract: Voltage-gated potassium (KV) channels, such as KCNQ1 (KV7.1), are modulated by accessory subunits and regulated by intracellular second messengers. Accessory subunits belonging to the KCNE family exert diverse functional effects on KCNQ1, have been ... ...

    Abstract Voltage-gated potassium (KV) channels, such as KCNQ1 (KV7.1), are modulated by accessory subunits and regulated by intracellular second messengers. Accessory subunits belonging to the KCNE family exert diverse functional effects on KCNQ1, have been implicated in the pathogenesis of various genetic disorders of heart rhythm, and contribute to transducing intracellular signaling events into changes in KV channel activity. We investigated the interactions between calmodulin (CaM), the ubiquitous Ca²⁺-transducing protein that binds and confers Ca²⁺ sensitivity to the biophysical properties of KCNQ1, and KCNE4. These studies were motivated by the observed similarities between the suppression of KCNQ1 function by pharmacological disruption of KCNQ1-CaM interactions and the effects of KCNE4 co-expression on the channel. We determined that KCNE4, but not KCNE1, can biochemically interact with CaM and that this interaction is Ca²⁺-dependent and requires a tetraleucine motif in the juxtamembrane region of the KCNE4 C terminus. Furthermore, disruption of the KCNE4-CaM interaction either by mutagenesis of the tetraleucine motif or by acute Ca²⁺ chelation impairs the ability of KCNE4 to inhibit KCNQ1. Our findings have potential relevance to KCNQ1 regulation both by KCNE accessory subunits and by an important intracellular signaling molecule.
    Language English
    Dates of publication 2011-0211
    Size p. 4141-4149.
    Publishing place American Society for Biochemistry and Molecular Biology
    Document type Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
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    Z 4' 65/118: Show issues
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  10. Article: Strategy for encoding and comparison of gene expression signatures

    Yi, Yajun / Alfred L George Jr / Chun Li / Clay Miller

    Genome biology. 2007 July, v. 8, no. 7

    2007  

    Abstract: EXALT (EXpression signature AnaLysis Tool) is a computational system enabling comparisons of microarray data across experimental platforms and different laboratories http://seq.mc.vanderbilt.edu/exalt/ . An essential feature of EXALT is a database ... ...

    Abstract EXALT (EXpression signature AnaLysis Tool) is a computational system enabling comparisons of microarray data across experimental platforms and different laboratories http://seq.mc.vanderbilt.edu/exalt/ . An essential feature of EXALT is a database holding thousands of gene expression signatures extracted from the Gene Expression Omnibus, and encoded in a searchable format. This novel approach to performing global comparisons of shared microarray data may have enormous value when coupled directly with a shared data repository.
    Keywords databases ; gene expression ; microarray technology
    Language English
    Dates of publication 2007-07
    Size p. 1614.
    Publishing place Springer-Verlag
    Document type Article
    ZDB-ID 2040529-7
    ISSN 1474-760X ; 1465-6914 ; 1465-6906
    ISSN (online) 1474-760X ; 1465-6914
    ISSN 1465-6906
    DOI 10.1186/gb-2007-8-7-r133
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