Modeling the Interactions Between Sodium Channels Provides Insight Into the Negative Dominance of Certain Channel Mutations

Hichri, Echrak; Selimi, Zoja; Kučera, Jan

doi:10.3389/fphys.2020.589386

Cited by 10 publications

(14 citation statements)

References 72 publications

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“…An assembly-mediated dominant-GOF mutation for heterozygous G375R can be compared to the well-known dominant-negative effect observed for some types of protein complexes and channelopathies ( Fink et al, 1996 ; Ribera et al, 1996 ; Silberberg et al, 2005 ; Reed et al, 2016 ; Du et al, 2020 ; Hichri et al, 2020 ; Backwell and Marsh, 2022 ). Both can cause disease through a disproportionate fraction of the channels affected.…”

Section: Discussionmentioning

confidence: 99%

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

Geng

Butler

et al. 2023

Journal of General Physiology

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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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Section: Discussionmentioning

confidence: 99%

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

Geng

Butler

et al. 2023

Journal of General Physiology

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“…Thus, the de novo heterozygous G375R mutation with respect to WT would induce its pathogenicity mainly through a dominant negative effect (31). Dominant negative mutations in BK and other ion channels have been described previously (28,(32)(33)(34)(35)(36), but this is the first time to our knowledge that the underling molecular mechanism has been revealed in such detail at the single channel level. For the G375R mutation heterozygous with WT, 85% of the expressed channels were heteromeric, and all these heteromeric channels displayed toxic properties (Figs.…”

Section: Discussionmentioning

confidence: 84%

“…A dominant-positive effect is an analogy 33 to the well-known dominant-negative effect observed for some types of protein complexes and channelopathies 33,[44][45][46][47][48][49] Both can cause disease: dominant positive from a GOF and dominant-negative from complete or partial LOF, and both have a disproportionate fraction of the channels affected.…”

Section: Discussionmentioning

confidence: 95%

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

Geng

Butler³

et al. 2021

Preprint

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De novo mutations play a prominent role in neurodevelopmental diseases including autism, schizophrenia, and intellectual disability. Many de novo mutations are dominant and so severe that the afflicted individuals do not reproduce, so the mutations are not passed into the general population. For multimeric proteins, such severity may result from a dominant-negative effect where mutant subunits assemble with WT to produce channels with adverse properties. Here we study the de novo variant G375R heterozygous with the WT allele for the large conductance voltage- and Ca2+-activated potassium (BK) channel, Slo1. This variant has been reported to produce devastating neurodevelopmental disorders in three unrelated children. If mutant and WT subunits assemble randomly to form tetrameric BK channels, then ~6% of the assembled channels would be wild type (WT), ~88% would be heteromeric incorporating from 1-3 mutant subunits per channel, and ~6% would be homomeric mutant channels consisting of four mutant subunits. To test this hypothesis, we analyzed the biophysical properties of single BK channels in the ensemble of channels expressed following a 1:1 injection of mutant and WT cRNA into oocytes. We found ~3% were WT channels, ~85% were heteromeric channels, and ~12% were homomeric mutant channels. All of the heteromeric channels as well as the homomeric mutant channels displayed toxic properties, indicating a dominant negative effect of the mutant subunits. The toxic channels were open at inappropriate negative voltages, even in the absence of Ca2+, which would lead to altered cellular function and decreased neuronal excitability.

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“…Finally, variants in Na v 1.7, which resulted in an alteration of the channel function when expressed alone, were rescued by their interaction with the WT α-subunits [28]. Very recently, the group of Dr. Kucera modeled the interactions between Na v channels in order to examine their consequences on channel kinetics and confirmed that, if the question remains open how variants interacting with WT channels affect the Na + current, the condition where a variant channel potentiates the current generated by the WT leading to a gain of function, is conceivable [29].…”

Section: Dysfunctional Channels Cooperated With Wt and With Each Othe...mentioning

confidence: 99%

Trafficking and Gating Cooperation Between Deficient Nav1.5-mutant Channels to Rescue INa

Clatot¹,

Coulombe²,

Deschênes³

et al. 2022

Front. Biosci. (Landmark Ed)

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Background: Pathogenic variants in SCN5A, the gene encoding the cardiac Na + channel α-subunit Nav1.5, result in life-threatening arrhythmias, e.g., Brugada syndrome, cardiac conduction defects and long QT syndrome. This variety of phenotypes is underlied by the fact that each Nav1.5 mutation has unique consequences on the channel trafficking and gating capabilities. Recently, we established that sodium channel α-subunits Nav1.5, Nav1.1 and Nav1.2 could dimerize, thus, explaining the potency of some Nav1.5 pathogenic variants to exert dominant-negative effect on WT channels, either by trafficking deficiency or coupled gating. Objective: The present study sought to examine whether Nav1.5 channels can cooperate, or transcomplement each other, to rescue the Na + current (INa). Such a mechanism could contribute to explain the genotype-phenotype discordance often observed in family members carrying Na + -channel pathogenic variants. Methods: Patch-clamp and immunocytochemistry analysis were used to investigate biophysical properties and cellular localization in HEK293 cells and rat neonatal cardiomyocytes transfected respectively with WT and 3 mutant channels chosen for their particular trafficking and/or gating properties. Results: As previously reported, the mutant channels G1743R and R878C expressed alone in HEK293 cells both abolished INa, G1743R through a trafficking deficiency and R878C through a gating deficiency. Here, we showed that coexpression of both G1743R and R878C nonfunctioning channels resulted in a partial rescue of INa, demonstrating a cooperative trafficking of Nav1.5 α-subunits. Surprisingly, we also showed a cooperation mechanism whereby the R878C gatingdeficient channel was able to rescue the slowed inactivation kinetics of the C-terminal truncated R1860X (∆Cter) variant, suggesting coupled gating. Conclusions: Altogether, our results add to the evidence that Nav channels are able to interact and regulate each other's trafficking and gating, a feature that likely contributes to explain the genotype-phenotype discordance often observed between members of a kindred carrying a Na + -channel pathogenic variant.

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Modeling the Interactions Between Sodium Channels Provides Insight Into the Negative Dominance of Certain Channel Mutations

Cited by 10 publications

References 72 publications

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

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

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

Trafficking and Gating Cooperation Between Deficient Nav1.5-mutant Channels to Rescue INa

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