| Autor: |
Zuccolo, E, Kheder, DA, Lim, D, Perna, A, Di Nezza, F, Botta, L, Scarpellino, G, Negri, S, Martinotti, S, Soda, T, Forcaia, G, Riboni, L, Ranzato, E, Sancini, G, Ambrosone, L, D'Angelo, E, Guerra, G, Moccia, F |
| Přispěvatelé: |
Zuccolo, E, Kheder, D, Lim, D, Perna, A, Di Nezza, F, Botta, L, Scarpellino, G, Negri, S, Martinotti, S, Soda, T, Forcaia, G, Riboni, L, Ranzato, E, Sancini, G, Ambrosone, L, D'Angelo, E, Guerra, G, Moccia, F |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
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| Popis: |
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 Ca 2+ concentration ([Ca 2+ ] i ) in the target cells, which activates the Ca 2+ /Calmodulin-dependent nitric oxide (NO) synthase to release NO. It is unclear whether brain endothelial cells also sense glutamate through an elevation in [Ca 2+ ] i and NO production. The current study assessed whether and how glutamate drives Ca 2+ -dependent NO release in bEND5 cells, an established model of brain endothelial cells. We found that glutamate induced a dose-dependent oscillatory increase in [Ca 2+ ] 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 Ca 2+ oscillations were triggered by rhythmic endogenous Ca 2+ mobilization and maintained over time by extracellular Ca 2+ entry. Pharmacological manipulation revealed that glutamate-induced endogenous Ca 2+ release was mediated by InsP 3 -sensitive receptors and nicotinic acid adenine dinucleotide phosphate (NAADP) gated two-pore channel 1. Constitutive store-operated Ca 2+ entry mediated Ca 2+ entry during ongoing Ca 2+ oscillations. Finally, glutamate evoked a robust, although delayed increase in NO levels, which was blocked by pharmacologically inhibition of the accompanying intracellular Ca 2+ signals. Of note, glutamate induced Ca 2+ -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 Ca 2+ oscillations and NO release have the potential to impact on neurovascular coupling in the brain. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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