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A reduction in SK channels contributes to increased activity of hypothalamic magnocellular neurons during heart failure


The Journal of Physiology

Published online on


Small conductance Ca2+‐activated K+ channels (SK) play an important role in regulating MNCs activity and hormone release from the posterior pituitary. Moreover, an enhanced SK activity contributes to MNCs’ adaptive responses to a physiological challenge, such as lactation. Still, whether changes in SK function/expression contribute to exacerbated MNCs activity during diseases like heart failure (HF), remains unknown. Here, we used a combination of patch‐clamp electrophysiology, confocal Ca2+ imaging and molecular biology in a rat model of ischemic HF. We found that the input‐output function of MNCs was enhanced in HF compared to sham rats. Moreover, while the SK blocker apamin (200 nm) strengthened the input‐output function in sham rats, it failed to have an effect in HF rats. The magnitude of the AHP following a train of spikes, and the underlying apamin‐sensitive IAHP were blunted in MNCs from HF rats. However, spike‐induced increases in intracellular Ca2+ were not affected in MNCs of HF rats. Real‐time PCR measurements of SK channel subunits mRNA in SON punches revealed a diminished expression of SK2/SK3 subunits in HF, compared to sham rats. Together, our studies demonstrate that MNCs from HF rats exhibit increased membrane excitability and an enhanced input‐output function, and that a reduction in SK channel‐mediated, apamin‐sensitive AHP is a critical contributing mechanism. Moreover, our results suggest that the reduced AHP is related to a down‐regulation of SK2/SK3 channel subunit expression, but not due to a blunted activity‐dependent intracellular Ca2+ increase following a burst of action potentials. This article is protected by copyright. All rights reserved