Altered NMDA receptor-evoked intracellular Ca2+ dynamics in magnocellular neurosecretory neurons of hypertensive rats

Meng Zhang, Javier Eduardo Stern

Research output: Contribution to journalArticle

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Abstract

Key points: NMDA receptor (NMDAR)-mediated Ca2+ signalling plays a critical role in modulating hypothalamic neurosecretory function. However, whether an altered NMDAR-evoked changes in Ca2+ (NMDAR-ΔCa2+) signalling in magnocellular neurosecretory cells (MNCs) may contribute to neurohumoral activation during disease states is unknown. We show that activation of NMDARs evoked similar inward currents in MNCs of sham and renovascular hypertensive (RVH) rats. Despite this, a prolonged and larger NMDAR-ΔCa2+ response was observed in the latter. The exacerbated NMDAR-ΔCa2+ responses in MNCs of RVH rats affected both somatic and dendritic compartments. Inhibition of the endoplasmic reticulum sarcoendoplasmic reticulum calcium trasport ATPase (SERCA) pump prolonged NMDAR-ΔCa2+ responses in sham rats, but not in RVH rats. Our study supports an altered spatiotemporal dynamic of NMDAR-ΔCa2+ signalling in MNCs from RVH rats, partly due to blunted endoplasmic reticulum Ca2+ buffering capacity. Abstract: A growing body of evidence supports an elevated NMDA receptor (NMDAR)-mediated glutamate excitatory function in the supraoptic nucleus and paraventricular nucleus of hypertensive rats that contributes to neurohumoral activation in this disease. However, the precise mechanisms underlying altered NMDAR signalling in hypertension remain to be elucidated. In this study, we performed simultaneous electrophysiology and fast confocal Ca2+ imaging to determine whether altered NMDAR-mediated changes in intracellular Ca2+ levels (NMDAR-ΔCa2+) occurred in hypothalamic magnocellular neurosecretory cells (MNCs) in renovascular hypertensive (RVH) rats. We found that despite evoking a similar excitatory inward current, activation of NMDARs resulted in a larger and prolonged ΔCa2+ in MNCs from RVH rats. Changes in NMDAR-ΔCa2+ dynamics were observed both in somatic and dendritic compartments. Inhibition of the sarcoendoplasmic reticulum calcium trasport ATPase (SERCA) pump activity with thapsigargin prolonged NMDAR-ΔCa2+ responses in MNCs of sham rats, but this effect was occluded in RVH rats, thus equalizing the magnitude and time course of the NMDA-ΔCa2+ responses between the two experimental groups. Taken together, our results support (1) an exacerbated NMDAR-ΔCa2+ response in somatodendritic compartments of MNCs of RVH rats, and (2) that a blunted ER Ca2+ buffering capacity contributes to the altered NMDAR-ΔCa2+ dynamics in this condition. Thus, altered spatiotemporal dynamics of the NMDAR-ΔCa2+ response stands as an underlying mechanism contributing to neurohumoral activation in neurogenic hypertension.

Original languageEnglish (US)
Pages (from-to)7399-7411
Number of pages13
JournalJournal of Physiology
Volume595
Issue number24
DOIs
StatePublished - Dec 15 2017

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N-Methyl-D-Aspartate Receptors
Neurons
Reticulum
Calcium-Transporting ATPases
Endoplasmic Reticulum
Hypertension
Supraoptic Nucleus
Thapsigargin
Paraventricular Hypothalamic Nucleus
Electrophysiology
N-Methylaspartate
Glutamic Acid

Keywords

  • NMDA
  • endoplasmic reticulum
  • glutamate
  • hypothalamus

ASJC Scopus subject areas

  • Physiology

Cite this

Altered NMDA receptor-evoked intracellular Ca2+ dynamics in magnocellular neurosecretory neurons of hypertensive rats. / Zhang, Meng; Stern, Javier Eduardo.

In: Journal of Physiology, Vol. 595, No. 24, 15.12.2017, p. 7399-7411.

Research output: Contribution to journalArticle

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