Impact of CaV1.3 L-Type Calcium Channels on Arrhythmogenesis in Cancer

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  Figure 1. Therapeutic Action and Cardiotoxic Side Effects of Doxorubicin (DOX). (Left) DOX acts as an anticancer drug by DNA intercalation in cancer cells. This leads to apoptosis and tumor regression. (Right) At the same time, DOX can enter the cardiomyocytes, activate death receptor pathways, and induce apoptosis. This results in cardiac tissue damage and reduced quality of life.

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  Figure 2. Structural and functional organization of voltage-gated calcium channels across tissues. (A) Classification of voltage-gated calcium channels (VGCCs) based on the pore-forming α1 subunit, corresponding human genes, current types, and voltage-activation thresholds. The CaV1 family (CaV1.1–CaV1.4) mediates L-type currents, the CaV2 family (CaV2.1–CaV2.3) mediates P/Q-, N-, and R-type currents, and the CaV3 family (CaV3.1–CaV3.3) mediates T-type currents. High-voltage-activated (HVA) and low-voltage-activated (LVA) channel families are indicated. (B) Topology of the α1 subunit. The α1 subunit contains four homologous domains (I–IV), each composed of six transmembrane segments (S1–S6). The S1–S4 segments form the voltage-sensing domain, whereas the S5–S6 segments and pore (P) loops form the calcium-selective pore. L-type calcium channel isoforms display tissue-specific expression profiles, with CaV1.1 primarily expressed in skeletal muscle; CaV1.2 and CaV1.3 are expressed in cardiac tissue, brain, endocrine organs, and vasculature; and CaV1.4 is predominantly expressed in the retina and immune cells. (C) Schematic representation of the VGCC complex showing the pore-forming α1 subunit…

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  Figure 3. Proposed mechanisms by which cancer and chemotherapy may differentially regulate CaV1.3 channels and contribute to arrhythmogenesis. (A) During cancer, CaV1.3 expression and function could be enhanced through increased PKA-, PKC-, and CaMKII-dependent phosphorylation, reduced ubiquitination, activation of HIF-1α signaling, increased CACNA1D transcription, decreased non-coding RNA (ncRNA), enhanced sarcoplasmic reticulum (SR) Ca2+ load, increased β-subunit availability, and increased basal cytosolic Ca2+. These changes could increase L-type Ca2+ current (ICa,L), promote sinoatrial (SA) and atrioventricular (AV) nodal excitability and conduction, and increase susceptibility to ectopy, tachycardia, and atrial fibrillation. (B) In contrast, chemotherapy-induced stress may reduce CaV1.3 expression and activity through decreased PKA signaling, increased ubiquitination, increase in HIF-1α signaling and cardiomyocyte injury, decreased CACNA1D transcription, increased ncRNA, reduced SR Ca2+ content, increased basal cytosolic Ca2+ overload, and loss of β-subunit support, resulting in decreased ICa,L, impaired SA and AV nodal function, reduced excitability and conduction, and an increased…

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  Figure 4. Causes of Arrhythmias in Cancer Patients. Arrhythmias in cancer patients may result from the cancer itself, anticancer therapies, or other contributing factors.