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An epilepsy-associa...
An epilepsy-associated KV1.2 charge-transfer-center mutation impairs KV1.2 and KV1.4 trafficking
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- Nilsson, Michelle (författare)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten,Pantazis
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- Lindström, Sarah H, 1977- (författare)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten
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- Kaneko, Maki (författare)
- Center for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, CA 90027;Division of Genomic Medicine, Department of Pathology, Children's Hospital Los Angeles, Los Angeles, CA 90027
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- Wang, Kaiqian (författare)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten
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- Minguez-Viñas, Teresa (författare)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten
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- Angelini, Marina (författare)
- Division of Molecular Medicine, Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
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- Steccanella, Federica (författare)
- Division of Molecular Medicine, Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
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- Holder, Deborah (författare)
- Comprehensive Epilepsy Program, Children's Hospital Los Angeles, Los Angeles, CA 90027
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- Ottolia, Michela (författare)
- Division of Molecular Medicine, Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
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- Olcese, Riccardo (författare)
- Division of Molecular Medicine, Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
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- Pantazis, Antonios, 1982- (författare)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten,Wallenberg Center for Molecular Medicine
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(creator_code:org_t)
- 2022-04-19
- 2022
- Engelska.
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:17
- Relaterad länk:
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https://doi.org/10.1...
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https://liu.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Significance: A child with epilepsy has a previously unreported, heterozygous mutation in KCNA2, the gene encoding KV1.2 proteins. Four KV1.2 assemble into a potassium-selective channel, a protein complex at the neuronal cell surface regulating electrical signaling. KV1.2 subunits assemble with other KV1-family members to form heterotetrameric channels, contributing to neuronal potassium-channel diversity. The most striking consequence of this mutation is preventing KV1.2-subunit trafficking, i.e., their ability to reach the cell surface. Moreover, the mutation is dominant negative, as mutant subunits can assemble with wild-type KV1.2 and KV1.4, trapping them into nontrafficking heterotetramers and decreasing their functional expression. Thus, KV1-family genes’ ability to form heterotetrameric channels is a double-edged sword, rendering KV1-family members vulnerable to dominant-negative mutations in a single member gene.Abstract: We report on a heterozygous KCNA2 variant in a child with epilepsy. KCNA2 encodes KV1.2 subunits, which form homotetrameric potassium channels and participate in heterotetrameric channel complexes with other KV1-family subunits, regulating neuronal excitability. The mutation causes substitution F233S at the KV1.2 charge transfer center of the voltage-sensing domain. Immunocytochemical trafficking assays showed that KV1.2(F233S) subunits are trafficking deficient and reduce the surface expression of wild-type KV1.2 and KV1.4: a dominant-negative phenotype extending beyond KCNA2, likely profoundly perturbing electrical signaling. Yet some KV1.2(F233S) trafficking was rescued by wild-type KV1.2 and KV1.4 subunits, likely in permissible heterotetrameric stoichiometries: electrophysiological studies utilizing applied transcriptomics and concatemer constructs support that up to one or two KV1.2(F233S) subunits can participate in trafficking-capable heterotetramers with wild-type KV1.2 or KV1.4, respectively, and that both early and late events along the biosynthesis and secretion pathway impair trafficking. These studies suggested that F233S causes a depolarizing shift of ∼48 mV on KV1.2 voltage dependence. Optical tracking of the KV1.2(F233S) voltage-sensing domain (rescued by wild-type KV1.2 or KV1.4) revealed that it operates with modestly perturbed voltage dependence and retains pore coupling, evidenced by off-charge immobilization. The equivalent mutation in the Shaker K+ channel (F290S) was reported to modestly affect trafficking and strongly affect function: an ∼80-mV depolarizing shift, disrupted voltage sensor activation and pore coupling. Our work exposes the multigenic, molecular etiology of a variant associated with epilepsy and reveals that charge-transfer-center disruption has different effects in KV1.2 and Shaker, the archetypes for potassium channel structure and function.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Physiology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biofysik (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biophysics (hsv//eng)
Nyckelord
- channelopathy
- dominant negative
- fluorometry
- ion channel
- trafficking
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Nilsson, Michell ...
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Lindström, Sarah ...
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Kaneko, Maki
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Wang, Kaiqian
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Minguez-Viñas, T ...
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Angelini, Marina
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Steccanella, Fed ...
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Holder, Deborah
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Ottolia, Michela
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Olcese, Riccardo
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Pantazis, Antoni ...
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