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A reduction in SK channels contributes to increased activity of hypothalamic magnocellular neurons during heart failure
Author(s) -
FerreiraNeto Hildebrando C.,
Biancardi Vinicia C.,
Stern Javier E.
Publication year - 2017
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp274730
Subject(s) - reduction (mathematics) , heart failure , medicine , neuroscience , cardiology , chemistry , endocrinology , biology , geometry , mathematics
Key points Small conductance Ca 2+ ‐activated K + (SK) channels play an important role in regulating the excitability of magnocellular neurosecretory cells (MNCs). Although an increased SK channel function contributes to adaptive physiological responses, it remains unknown whether changes in SK channel function/expression contribute to exacerbated MNC activity under disease conditions. We show that the input–output function of MNCs in heart failure (HF) rats is enhanced. Moreover, the SK channel blocker apamin enhanced the input–output function in sham, although not in HF rats. We found that both the after‐hyperpolarizing potential magnitude and the underlying apamin‐sensitive I AHP are blunted in MNCs from HF rats. The magnitude of spike‐induced increases in intracellular Ca 2+ levels was not affected in MNCs of HF rats. We found a diminished expression of SK2/SK3 channel subunit mRNA expression in the supraoptic nucleus of HF rats. Our studies suggest that a reduction in SK channel expression, but not changes in Ca 2+ ‐mediated activation of SK channels, contributes to exacerbated MNC activity in HF rats.Abstract Small conductance Ca 2+ ‐activated K + channels (SK) play an important role in regulating the activity of magnocellular neurosecretory cells (MNCs) and hormone release from the posterior pituitary. Moreover, enhanced SK activity contributes to the adaptive responses of MNCs to physiological challenge, such as lactation. Nevertheless, whether changes in SK function/expression contribute to exacerbated MNC activity during diseases such as heart failure (HF) remains unknown. In the present study, we used a combination of patch clamp electrophysiology, confocal Ca 2+ imaging and molecular biology in a rat model of ischaemic HF. We found that the input–output function of MNCs was enhanced in HF compared to sham rats. Moreover, although the SK blocker apamin (200 n m ) strengthened the input–output function in sham rats, it failed to have an effect in HF rats. The magnitude of the after‐hyperpolarizing potential (AHP) following a train of spikes and the underlying apamin‐sensitive I AHP were blunted in MNCs from HF rats. However, spike‐induced increases in intracellular Ca 2+ were not affected in the MNCs of HF rats. Real‐time PCR measurements of SK channel subunits mRNA in supraoptic nucleus 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 also 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 the result of a blunted activity‐dependent intracellular Ca 2+ increase following a burst of action potentials.