Abstract Body: The COVID-19 pandemic has highlighted the impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) on cardiovascular health, with long COVID symptoms such as arrhythmias and heart failure persisting globally. Cardiac injury in hospitalized patients worsens outcomes, underscoring the need to study how SARS-CoV-2, particularly its spike protein, affects cardiac function and arrhythmogenic risk. Given the spike protein’s role in viral entry and potential ion channel interactions, its impact on cardiac electrophysiology warrants investigation.
Ion channels regulate the cardiomyocyte membrane potential, and their dysregulation can lead to arrhythmias. RNA Sequencing (RNA-Seq) analysis of spike protein-expressing mouse hearts revealed differential ion channel expression, though key channels for action potential generation remained largely unchanged. AlphaFold modeling identified the Potassium Voltage Gated Channel Subfamily A Member 5 (KCNA5) as a key SARS-CoV-2 spike protein binding partner among cardiac ion channels. As a critical potassium channel governing repolarization, KCNA5 dysfunction is linked to atrial fibrillation (AF), a condition that can exacerbate COVID-19 outcomes. This study reveals that the spike protein enhances KCNA5 currents, potentially increasing arrhythmia susceptibility, while the E3 ubiquitin ligase Membrane Associated Ring-CH-Type Finger 2 (MARCHF2) emerges as a candidate for spike protein degradation. E3 ligases, which regulate protein stability through ubiquitination, may offer novel antiviral strategies by targeting viral-host protein interactions. Our findings establish: (1) a direct spike-KCNA5 interaction contributes to cardiac electrical disturbances, and (2) the therapeutic potential of E3 ligases in modulating these effects. These insights bridge molecular mechanisms (spike-induced ion channel modulation) with clinical implications (COVID-19-associated arrhythmias), highlighting translational opportunities such as targeting KCNA5-spike interactions to prevent electrical abnormalities and harnessing E3 ligases like MARCHF2 to reduce viral protein load.