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BK channels of five different subunit combinations underlie the de novo KCNMA1 G375R channelopathy

The molecular basis of a severe developmental and neurological disorder associated with a de novo G375R variant of the tetrameric BK channel is unknown. Here, we address this question by recording from single BK channels expressed to mimic a G375R mutation heterozygous with a WT allele. Five differe...

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Autores principales: Geng, Yanyan, Li, Ping, Butler, Alice, Wang, Bill, Salkoff, Lawrence, Magleby, Karl L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10067970/
https://www.ncbi.nlm.nih.gov/pubmed/36995317
http://dx.doi.org/10.1085/jgp.202213302
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author Geng, Yanyan
Li, Ping
Butler, Alice
Wang, Bill
Salkoff, Lawrence
Magleby, Karl L.
author_facet Geng, Yanyan
Li, Ping
Butler, Alice
Wang, Bill
Salkoff, Lawrence
Magleby, Karl L.
author_sort Geng, Yanyan
collection PubMed
description The molecular basis of a severe developmental and neurological disorder associated with a de novo G375R variant of the tetrameric BK channel is unknown. Here, we address this question by recording from single BK channels expressed to mimic a G375R mutation heterozygous with a WT allele. Five different types of functional BK channels were expressed: 3% were consistent with WT, 12% with homotetrameric mutant, and 85% with three different types of hybrid (heterotetrameric) channels assembled from both mutant and WT subunits. All channel types except WT showed a marked gain-of-function in voltage activation and a smaller decrease-of-function in single-channel conductance, with both changes in function becoming more pronounced as the number of mutant subunits per tetrameric channel increased. The net cellular response from the five different types of channels comprising the molecular phenotype was a shift of −120 mV in the voltage required to activate half of the maximal current through BK channels, giving a net gain-of-function. The WT and homotetrameric mutant channels in the molecular phenotype were consistent with genetic codominance as each displayed properties of a channel arising from only one of the two alleles. The three types of hybrid channels in the molecular phenotype were consistent with partial dominance as their properties were intermediate between those of mutant and WT channels. A model in which BK channels randomly assemble from mutant and WT subunits, with each subunit contributing increments of activation and conductance, approximated the molecular phenotype of the heterozygous G375R mutation.
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spelling pubmed-100679702023-04-04 BK channels of five different subunit combinations underlie the de novo KCNMA1 G375R channelopathy Geng, Yanyan Li, Ping Butler, Alice Wang, Bill Salkoff, Lawrence Magleby, Karl L. J Gen Physiol Article The molecular basis of a severe developmental and neurological disorder associated with a de novo G375R variant of the tetrameric BK channel is unknown. Here, we address this question by recording from single BK channels expressed to mimic a G375R mutation heterozygous with a WT allele. Five different types of functional BK channels were expressed: 3% were consistent with WT, 12% with homotetrameric mutant, and 85% with three different types of hybrid (heterotetrameric) channels assembled from both mutant and WT subunits. All channel types except WT showed a marked gain-of-function in voltage activation and a smaller decrease-of-function in single-channel conductance, with both changes in function becoming more pronounced as the number of mutant subunits per tetrameric channel increased. The net cellular response from the five different types of channels comprising the molecular phenotype was a shift of −120 mV in the voltage required to activate half of the maximal current through BK channels, giving a net gain-of-function. The WT and homotetrameric mutant channels in the molecular phenotype were consistent with genetic codominance as each displayed properties of a channel arising from only one of the two alleles. The three types of hybrid channels in the molecular phenotype were consistent with partial dominance as their properties were intermediate between those of mutant and WT channels. A model in which BK channels randomly assemble from mutant and WT subunits, with each subunit contributing increments of activation and conductance, approximated the molecular phenotype of the heterozygous G375R mutation. Rockefeller University Press 2023-03-30 /pmc/articles/PMC10067970/ /pubmed/36995317 http://dx.doi.org/10.1085/jgp.202213302 Text en © 2023 Geng et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Geng, Yanyan
Li, Ping
Butler, Alice
Wang, Bill
Salkoff, Lawrence
Magleby, Karl L.
BK channels of five different subunit combinations underlie the de novo KCNMA1 G375R channelopathy
title BK channels of five different subunit combinations underlie the de novo KCNMA1 G375R channelopathy
title_full BK channels of five different subunit combinations underlie the de novo KCNMA1 G375R channelopathy
title_fullStr BK channels of five different subunit combinations underlie the de novo KCNMA1 G375R channelopathy
title_full_unstemmed BK channels of five different subunit combinations underlie the de novo KCNMA1 G375R channelopathy
title_short BK channels of five different subunit combinations underlie the de novo KCNMA1 G375R channelopathy
title_sort bk channels of five different subunit combinations underlie the de novo kcnma1 g375r channelopathy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10067970/
https://www.ncbi.nlm.nih.gov/pubmed/36995317
http://dx.doi.org/10.1085/jgp.202213302
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