Glutamate triggers intracellular Ca 2+ oscillations and nitric oxide release by inducing NAADP- and InsP 3 -dependent Ca 2+ release in mouse brain endothelial cells
Articolo
Data di Pubblicazione:
2019
Citazione:
Glutamate triggers intracellular Ca 2+ oscillations and nitric oxide release by inducing NAADP- and InsP 3 -dependent Ca 2+ release in mouse brain endothelial cells / E. Zuccolo, D.A. Kheder, D. Lim, A. Perna, F.D. Nezza, L. Botta, G. Scarpellino, S. Negri, S. Martinotti, T. Soda, G. Forcaia, L. Riboni, E. Ranzato, G. Sancini, L. Ambrosone, E. D'Angelo, G. Guerra, F. Moccia. - In: JOURNAL OF CELLULAR PHYSIOLOGY. - ISSN 0021-9541. - 234:4(2019 Apr), pp. 3538-3554. [10.1002/jcp.26953]
Abstract:
The neurotransmitter glutamate increases cerebral blood flow by activating postsynaptic neurons and presynaptic glial cells within the neurovascular unit. Glutamate does so by causing an increase in intracellular Ca2+ concentration ([Ca2+ ]i ) in the target cells, which activates the Ca2+ /Calmodulin-dependent nitric oxide (NO) synthase to release NO. It is unclear whether brain endothelial cells also sense glutamate through an elevation in [Ca2+ ]i and NO production. The current study assessed whether and how glutamate drives Ca2+ -dependent NO release in bEND5 cells, an established model of brain endothelial cells. We found that glutamate induced a dose-dependent oscillatory increase in [Ca2+ ]i , which was maximally activated at 200 μM and inhibited by α-methyl-4-carboxyphenylglycine, a selective blocker of Group 1 metabotropic glutamate receptors. Glutamate-induced intracellular Ca2+ oscillations were triggered by rhythmic endogenous Ca2+ mobilization and maintained over time by extracellular Ca2+ entry. Pharmacological manipulation revealed that glutamate-induced endogenous Ca2+ release was mediated by InsP3 -sensitive receptors and nicotinic acid adenine dinucleotide phosphate (NAADP) gated two-pore channel 1. Constitutive store-operated Ca2+ entry mediated Ca2+ entry during ongoing Ca2+ oscillations. Finally, glutamate evoked a robust, although delayed increase in NO levels, which was blocked by pharmacologically inhibition of the accompanying intracellular Ca2+ signals. Of note, glutamate induced Ca2+ -dependent NO release also in hCMEC/D3 cells, an established model of human brain microvascular endothelial cells. This investigation demonstrates for the first time that metabotropic glutamate-induced intracellular Ca2+ oscillations and NO release have the potential to impact on neurovascular coupling in the brain.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Ca2+ oscillations; endothelial cells; glutamate; neurovascular coupling (NVC); nitric oxide
Elenco autori:
E. Zuccolo, D.A. Kheder, D. Lim, A. Perna, F.D. Nezza, L. Botta, G. Scarpellino, S. Negri, S. Martinotti, T. Soda, G. Forcaia, L. Riboni, E. Ranzato, G. Sancini, L. Ambrosone, E. D'Angelo, G. Guerra, F. Moccia
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