Journal of molecular and cellular cardiology · 2026
Functional recruitment and regulatory mechanisms of SK channels in patients with early stages of ventricular remodeling.
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Pérez-Martínez Alba, López-Andrés Cristina, García-Mendívil Laura, López-Yus Marta, Batín Diana, Vallejo-Gil Jose M, Fañanás-Mastral Javier, Vázquez-Sancho Manuel, Matamala-Adell Marta, Sorribas-Berjón Juan F, Bellido-Morales Javier A, Ballester-Cuenca Carlos, Arbonés Mainar Jose M, Pueyo Esther, Oliván-Viguera Aída
Аннотация
AIMS: Small-conductance Ca2+-activated potassium channels (SK) are increasingly investigated as therapeutic targets for atrial fibrillation. Emerging evidence, however, indicates their functional relevance in ventricular pathologies. This study investigates the expression, localization, and functional role of SK2 and SK3 channel subtypes in ventricular myocardium from patients with and without valvular disease-associated remodeling.
METHODS AND RESULTS: Human ventricular tissue was obtained from 125 patients undergoing cardiac surgery. mRNA levels of KCNN2 and KCNN3 were quantified with RT-qPCR. Protein levels and localization of SK2 and SK3 were analyzed via immunohistochemistry. Functional responses were evaluated by optical mapping of living ventricular myocardial slices. Gene expression was not significantly altered in remodeled myocardium. SK2 and SK3 were located in striated patterns, colocalizing with L-type Ca2+ channels in all patients. SK3 was also present at intercalated discs, although this pattern was significantly reduced in remodeled myocardium. Functionally, SK channels were inactive in non-remodeled myocardium, with neither apamin nor SKA-31 altering action potential duration (APD). In contrast, in remodeled myocardium, apamin prolonged and SKA-31 shortened APD. This response to SKA-31 was more pronounced in patients with reduced ejection fraction. Mechanistically, SKA-31 effects were abolished by L-type Ca2+ channel blockade or CaMKII inhibition, but not by PKA inhibition, suggesting that SK activation is Ca2+ and CaMKII-dependent.
CONCLUSIONS: SK channels become functionally upregulated in the early stages of ventricular remodeling despite the absence of gene expression changes. SK activation might rely on post-translational modifications and calcium handling alterations. These findings highlight the need for caution in targeting SK channels therapeutically.
METHODS AND RESULTS: Human ventricular tissue was obtained from 125 patients undergoing cardiac surgery. mRNA levels of KCNN2 and KCNN3 were quantified with RT-qPCR. Protein levels and localization of SK2 and SK3 were analyzed via immunohistochemistry. Functional responses were evaluated by optical mapping of living ventricular myocardial slices. Gene expression was not significantly altered in remodeled myocardium. SK2 and SK3 were located in striated patterns, colocalizing with L-type Ca2+ channels in all patients. SK3 was also present at intercalated discs, although this pattern was significantly reduced in remodeled myocardium. Functionally, SK channels were inactive in non-remodeled myocardium, with neither apamin nor SKA-31 altering action potential duration (APD). In contrast, in remodeled myocardium, apamin prolonged and SKA-31 shortened APD. This response to SKA-31 was more pronounced in patients with reduced ejection fraction. Mechanistically, SKA-31 effects were abolished by L-type Ca2+ channel blockade or CaMKII inhibition, but not by PKA inhibition, suggesting that SK activation is Ca2+ and CaMKII-dependent.
CONCLUSIONS: SK channels become functionally upregulated in the early stages of ventricular remodeling despite the absence of gene expression changes. SK activation might rely on post-translational modifications and calcium handling alterations. These findings highlight the need for caution in targeting SK channels therapeutically.