Mechanisms and physiological implications of cooperative gating of clustered ion channels

Dixon, Rose E.; Navedo, Manuel F.; Binder, Marc D.; Santana, Luis Fernando

doi:10.1152/physrev.00022.2021

Cited by 68 publications

(58 citation statements)

References 460 publications

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“…As reported recently in the excellent review from Dixon et al [24], many recent experimental findings provided evidence that several classes of ion channels appear to open and close in a coordinated, cooperative manner. Considering the cardiac Na + channel Na v 1.5, we published the first evidence that the BrS Na v 1.5-L325R mutant dimerized with WT channels and led to a dominant negative effect by coupled gating [11].…”

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

confidence: 75%

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

confidence: 75%

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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“…Functional ion channel partnerships established by a close spatial association of ion channel pairs or higher-order oligomers have been reported for many voltage-gated ion channels. Homomeric ion channel complexes are described for VGCCs, voltage-gated Na + channels, and voltage-gated K + channels (for a detailed review, see [21]). In many such cases, channel oligomerization serves a key role in permitting physical interactions between channels to modulate gating properties, tuning electrical activity.…”

Section: Canonical Ion Channel Partnershipsmentioning

confidence: 99%

Ion Channel Partnerships: Odd and Not-So-Odd Couples Controlling Neuronal Ion Channel Function

Vierra

Trimmer

2022

IJMS

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The concerted function of the large number of ion channels expressed in excitable cells, including brain neurons, shapes diverse signaling events by controlling the electrical properties of membranes. It has long been recognized that specific groups of ion channels are functionally coupled in mediating ionic fluxes that impact membrane potential, and that these changes in membrane potential impact ion channel gating. Recent studies have identified distinct sets of ion channels that can also physically and functionally associate to regulate the function of either ion channel partner beyond that afforded by changes in membrane potential alone. Here, we review canonical examples of such ion channel partnerships, in which a Ca2+ channel is partnered with a Ca2+-activated K+ channel to provide a dedicated route for efficient coupling of Ca2+ influx to K+ channel activation. We also highlight examples of non-canonical ion channel partnerships between Ca2+ channels and voltage-gated K+ channels that are not intrinsically Ca2+ sensitive, but whose partnership nonetheless yields enhanced regulation of one or the other ion channel partner. We also discuss how these ion channel partnerships can be shaped by the subcellular compartments in which they are found and provide perspectives on how recent advances in techniques to identify proteins in close proximity to one another in native cells may lead to an expanded knowledge of other ion channel partnerships.

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“…To attain a more complete view of the factors that contribute to Ca 2+ influx variability, we must also consider Ca 2+ entry via Ca V 1.2 channel clusters, as recent studies suggest that the activity of these channels is critically dependent on their spatial organization (reviewed by Dixon et al [2021] ). Clustered Ca V 1.2 channels physically interact via their C-terminal tails, an interaction that is tightly regulated by local and global [Ca 2+ ] i .…”

Section: Fluctuations In Ca V 12 Conductance Durin...mentioning

confidence: 99%

Biological noise is a key determinant of the reproducibility and adaptability of cardiac pacemaking and EC coupling

Guarina

Moghbel

Pourhosseinzadeh

et al. 2022

Journal of General Physiology

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Each heartbeat begins with the generation of an action potential in pacemaking cells in the sinoatrial node. This signal triggers contraction of cardiac muscle through a process termed excitation–contraction (EC) coupling. EC coupling is initiated in dyadic structures of cardiac myocytes, where ryanodine receptors in the junctional sarcoplasmic reticulum come into close apposition with clusters of CaV1.2 channels in invaginations of the sarcolemma. Cooperative activation of CaV1.2 channels within these clusters causes a local increase in intracellular Ca2+ that activates the juxtaposed ryanodine receptors. A salient feature of healthy cardiac function is the reliable and precise beat-to-beat pacemaking and amplitude of Ca2+ transients during EC coupling. In this review, we discuss recent discoveries suggesting that the exquisite reproducibility of this system emerges, paradoxically, from high variability at subcellular, cellular, and network levels. This variability is attributable to stochastic fluctuations in ion channel trafficking, clustering, and gating, as well as dyadic structure, which increase intracellular Ca2+ variance during EC coupling. Although the effects of these large, local fluctuations in function and organization are sometimes negligible at the macroscopic level owing to spatial–temporal summation within and across cells in the tissue, recent work suggests that the “noisiness” of these intracellular Ca2+ events may either enhance or counterintuitively reduce variability in a context-dependent manner. Indeed, these noisy events may represent distinct regulatory features in the tuning of cardiac contractility. Collectively, these observations support the importance of incorporating experimentally determined values of Ca2+ variance in all EC coupling models. The high reproducibility of cardiac contraction is a paradoxical outcome of high Ca2+ signaling variability at subcellular, cellular, and network levels caused by stochastic fluctuations in multiple processes in time and space. This underlying stochasticity, which counterintuitively manifests as reliable, consistent Ca2+ transients during EC coupling, also allows for rapid changes in cardiac rhythmicity and contractility in health and disease.

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Mechanisms and physiological implications of cooperative gating of clustered ion channels

Cited by 68 publications

References 460 publications

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

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

Ion Channel Partnerships: Odd and Not-So-Odd Couples Controlling Neuronal Ion Channel Function

Biological noise is a key determinant of the reproducibility and adaptability of cardiac pacemaking and EC coupling

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