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

Small conductance Ca2+ -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 Ca2+ 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 nm) 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 IAHP were blunted in MNCs from HF rats. However, spike-induced increases in intracellular Ca2+ 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 Ca2+ increase following a burst of action potentials.