Glutamate gradually elevates [Zn(2+)](i) via the CaM-CaMKII-NOS cascade in primary cultured rat embryonic cortical neurons.

Zn(2+) is essential for neuronal signaling, but imbalance cause cell death and neurodegenerative disorders. While the buffering system maintains low cytosolic Zn(2+) concentration ([Zn(2+)](i)), the details on physiological stimuli elevating [Zn(2+)](i) for neuronal processes remain limited. Our previous reports have demonstrated that dopamine elevates [Zn(2+)](i) through the cAMP-NO pathway, activating autophagy and inflammation in neurons. In this study, we adopted the Zn(2+) imaging technique to verify how glutamate elevated [Zn(2+)](i) in cultured cortical neurons and examined the inflammatory response. Our results showed that glutamate elevates the [Zn(2+)](i), by activating ionotropic glutamate receptors. Inhibitors of calmodulin (CaM), CaM-dependent protein kinase II (CaMKII), and NO synthase (NOS) blocked the glutamate-induced Zn(2+) response. High-K(+) buffer induced-membrane depolarization significantly elevated the intracellular Ca(2+) concentration ([Ca(2+)](i)) but only slightly increased [Zn(2+)](i) and NO production. Glutamate also transiently increased NOS phosphorylation at Ser(1417) within 15 min. The Zn(2+) chelator, TPEN suppressed glutamate-induced inflammasome formation. These results indicate that glutamate-induced local increment in [Ca(2+)](i) via the ionotropic glutamate receptors activates the CaM-CaMKII-NOS complex to produce NO and elevate [Zn(2+)](i). which trigger inflammation in cultured neurons. Henceforth, this novel glutamate-Zn(2+) signaling pathway after glutamate depolarization elevates [Ca(2+)](i) indicates the involvement of Zn(2+) in modulating long-term neuronal activities.