Microtubule plus-end tracking proteins: novel modulators of cardiac sodium channels and arrhythmogenesis

Gerard A. Marchal*, Niels Galjart, Vincent Portero, Carol Ann Remme*

*Corresponding author for this work

Research output: Contribution to journalReview articleAcademicpeer-review

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Abstract

The cardiac sodium channel NaV1.5 is an essential modulator of cardiac excitability, with decreased NaV1.5 levels at the plasma membrane and consequent reduction in sodium current (INa) leading to potentially lethal cardiac arrhythmias. NaV1.5 is distributed in a specific pattern at the plasma membrane of cardiomyocytes, with localization at the crests, grooves, and T-tubules of the lateral membrane and particularly high levels at the intercalated disc region. NaV1.5 forms a large macromolecular complex with and is regulated by interacting proteins, some of which are specifically localized at either the lateral membrane or intercalated disc. One of the NaV1.5 trafficking routes is via microtubules (MTs), which are regulated by MT plus-end tracking proteins (+TIPs). In our search for mechanisms involved in targeted delivery of NaV1.5, we here provide an overview of previously demonstrated interactions between NaV1.5 interacting proteins and +TIPs, which potentially (in)directly impact on NaV1.5 trafficking. Strikingly, +TIPs interact extensively with several intercalated disc- and lateral membrane-specific NaV1.5 interacting proteins. Recent work indicates that this interplay of +TIPs and NaV1.5 interacting proteins mediates the targeted delivery of NaV1.5 at specific cardiomyocyte subcellular domains, while also being potentially relevant for the trafficking of other ion channels. These observations are especially relevant for diseases associated with loss of NaV1.5 specifically at the lateral membrane (such as Duchenne muscular dystrophy), or at the intercalated disc (for example, arrhythmogenic cardiomyopathy), and open up potential avenues for development of new anti-arrhythmic therapies.

Original languageEnglish
Pages (from-to)1461-1479
Number of pages19
JournalCardiovascular Research
Volume119
Issue number7
DOIs
Publication statusPublished - 1 Jun 2023

Bibliographical note

Funding Information:
C.A.R. is supported by Fondation Leducq (17CVD02), the Netherlands CardioVascular Research Initiative (CVON): the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, the Royal Netherlands Academy of Sciences (CVON-eDETECT 2015-12, CVON-PREDICT2 2018-30), and the Netherlands Organization for Health Research and Development (ZonMw; Innovational Research Incentives Scheme Vidi grant 91714371.

Publisher Copyright:
© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.

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