Glutamate gradually elevates [Zn2+]i via the CaM–CaMKII–NOS cascade in primary cultured rat embryonic cortical neurons
Journal
Scientific Reports
Journal Volume
15
Journal Issue
1
Start Page
Article number 15205
ISSN
2045-2322
Date Issued
2025-04-30
Author(s)
Abstract
Zn2+ is essential for neuronal signaling, but imbalance cause cell death and neurodegenerative disorders. While the buffering system maintains low cytosolic Zn2+ concentration ([Zn2+]i), the details on physiological stimuli elevating [Zn2+]i for neuronal processes remain limited. Our previous reports have demonstrated that dopamine elevates [Zn2+]i through the cAMP−NO pathway, activating autophagy and inflammation in neurons. In this study, we adopted the Zn2+ imaging technique to verify how glutamate elevated [Zn2+]i in cultured cortical neurons and examined the inflammatory response. Our results showed that glutamate elevates the [Zn2+]i, by activating ionotropic glutamate receptors. Inhibitors of calmodulin (CaM), CaM-dependent protein kinase II (CaMKII), and NO synthase (NOS) blocked the glutamate-induced Zn2+ response. High-K+ buffer induced-membrane depolarization significantly elevated the intracellular Ca2+ concentration ([Ca2+]i) but only slightly increased [Zn2+]i and NO production. Glutamate also transiently increased NOS phosphorylation at Ser1417 within 15 min. The Zn2+ chelator, TPEN suppressed glutamate-induced inflammasome formation. These results indicate that glutamate-induced local increment in [Ca2+]i via the ionotropic glutamate receptors activates the CaM−CaMKII−NOS complex to produce NO and elevate [Zn2+]i. which trigger inflammation in cultured neurons. Henceforth, this novel glutamate−Zn2+ signaling pathway after glutamate depolarization elevates [Ca2+]i indicates the involvement of Zn2+ in modulating long-term neuronal activities.
Subjects
Calmodulin
Calmodulin-dependent protein kinase II
Inflammation
Ionotropic glutamate receptor
Nitric oxide synthase
Zn2+
SDGs
Publisher
Springer Science and Business Media LLC
Type
journal article