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Ion channel trafficking implications in heart failure - PubMed

  • ️Mon Jan 01 2024

Review

Ion channel trafficking implications in heart failure

Jean-Baptiste Reisqs et al. Front Cardiovasc Med. 2024.

Abstract

Heart failure (HF) is recognized as an epidemic in the contemporary world, impacting around 1%-2% of the adult population and affecting around 6 million Americans. HF remains a major cause of mortality, morbidity, and poor quality of life. Several therapies are used to treat HF and improve the survival of patients; however, despite these substantial improvements in treating HF, the incidence of HF is increasing rapidly, posing a significant burden to human health. The total cost of care for HF is USD 69.8 billion in 2023, warranting a better understanding of the mechanisms involved in HF. Among the most serious manifestations associated with HF is arrhythmia due to the electrophysiological changes within the cardiomyocyte. Among these electrophysiological changes, disruptions in sodium and potassium currents' function and trafficking, as well as calcium handling, all of which impact arrhythmia in HF. The mechanisms responsible for the trafficking, anchoring, organization, and recycling of ion channels at the plasma membrane seem to be significant contributors to ion channels dysfunction in HF. Variants, microtubule alterations, or disturbances of anchoring proteins lead to ion channel trafficking defects and the alteration of the cardiomyocyte's electrophysiology. Understanding the mechanisms of ion channels trafficking could provide new therapeutic approaches for the treatment of HF. This review provides an overview of the recent advances in ion channel trafficking in HF.

Keywords: arrhythmia; electrophysiology; heart failure; ion channels; trafficking; treatment.

© 2024 Reisqs, Qu and Boutjdir.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1

Arrhythmogenesis mechanisms in heart failure. (A) In HF condition, decrease of K+ current (Ito, IKr, IKs) and/or INaL can prolong the AP. This remodeling triggers EADs. (B) In addition, intracellular Ca2+ overload during the diastole can trigger DADs. This is due to an increase in NCX reverse mode, Ca2+ leak from the RYR2, and a decrease of SERCA function. (C) The remodeling of Cx43 and/or decrease of INa contribute to slowing the conduction velocity and APD heterogeneity, which creates conduction block and promotes re-entry pathways. AP, action potential; EADs, early aftredepolarizations; DADs, delayed aftredepolarizations; NCX, Na+/Ca2+ exchanger; RYR2, ryanodine receptor 2; SERCA, Sarcoendoplasmic Reticulum Calcium ATPase; Cx43, connexin 43; APD, action potential duration.

Figure 2
Figure 2

Schematic representation of ion channels trafficking. (A) The newly synthesized proteins in the ER are carried by the COPII vesicles until the Golgi apparatus in the anterograde direction. (B) In cases where the assembly of the newly synthesized protein is misfolded, it is retained in the ER followed by the activation of the UPR and ERAD to allow its degradation in the cytosol. (C) After the final maturation process, the new ion channel protein is directed to the plasma membrane by a vesicle. At the final localization, the v-SNARE and t-SNARE proteins interact to allow the fusion between the vesicle and the plasma membrane. (D) Then the ion channel is recaptured into the cell by endocytosis and carried out by a vesicle with Rab4/5 protein and dynein to allow the retrograde direction. (E) The ion channel is transported by a late vesicle with Rab7/9 protein and degraded in the cytosol, or (F) is recycled by another vesicle with the Rab11 protein. (G) The final step of the ion channel trafficking is carried out by the COPI vesicle for the retrograde direction to be recycled into the ER. It is important to note that the accessory molecules, such as CASK and SAP97, stabilize the ion channel at the destination.

Figure 3
Figure 3

Ion channels trafficking perturbation in heart failure. (A) Ion channel variant leads to ER retention of the ion channel. (B) PTM alteration triggers the ion channel retention in the ER and the degradation of the ion channel. (C) ER stress leads to an abnormal degradation of the ion channel protein by the UPR response. (D) The detyrosination of the microtubules alters the ion channel trafficking. (E) Alteration of EB1 or BIN1 inhibits the ion channel incorporation into the membrane. (F) Hypokalemia triggers an abnormal ubiquitination of hERG and its degradation. (G) Decrease of HSP90 chaperone disturbs the K+ channel trafficking. (H) Decrease of synapsin2 vesicle decreases the trafficking of NCX. PTM, post-translational modification.

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