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

Hildebrando C. Ferreira-Neto, Vinicia Campana Biancardi, Javier Eduardo Stern

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Key points: Small conductance Ca2+-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 IAHP are blunted in MNCs from HF rats. The magnitude of spike-induced increases in intracellular Ca2+ 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 Ca2+-mediated activation of SK channels, contributes to exacerbated MNC activity in HF rats. Abstract: 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.

Original languageEnglish (US)
Pages (from-to)6429-6442
Number of pages14
JournalJournal of Physiology
Volume595
Issue number20
DOIs
StatePublished - Oct 15 2017

Fingerprint

Heart Failure
Neurons
Apamin
Calcium-Activated Potassium Channels
Supraoptic Nucleus
Posterior Pituitary Hormones
Messenger RNA
Electrophysiology
Lactation
Action Potentials
Real-Time Polymerase Chain Reaction
Molecular Biology
Down-Regulation
Membranes

Keywords

  • Calcium
  • oxytocin
  • potassium
  • supraoptic
  • vasopressin

ASJC Scopus subject areas

  • Physiology

Cite this

A reduction in SK channels contributes to increased activity of hypothalamic magnocellular neurons during heart failure. / Ferreira-Neto, Hildebrando C.; Biancardi, Vinicia Campana; Stern, Javier Eduardo.

In: Journal of Physiology, Vol. 595, No. 20, 15.10.2017, p. 6429-6442.

Research output: Contribution to journalArticle

Ferreira-Neto, Hildebrando C. ; Biancardi, Vinicia Campana ; Stern, Javier Eduardo. / A reduction in SK channels contributes to increased activity of hypothalamic magnocellular neurons during heart failure. In: Journal of Physiology. 2017 ; Vol. 595, No. 20. pp. 6429-6442.
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AU - Biancardi, Vinicia Campana

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N2 - Key points: Small conductance Ca2+-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 IAHP are blunted in MNCs from HF rats. The magnitude of spike-induced increases in intracellular Ca2+ 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 Ca2+-mediated activation of SK channels, contributes to exacerbated MNC activity in HF rats. Abstract: 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.

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