Dopamine Activates the D1R-Zn2+ Signaling Pathway to Trigger Inflammatory Response in Primary-Cultured Rat Embryonic Cortical Neurons

• Published in: Cellular and molecular neurobiology 2023-10, Vol.43 (7), p.3593-3604
• Main Authors: Tseng, Hui-Chiun, Pan, Chien-Yuan
• Format: Article
• Language: English
• Subjects: Apoptosis; Autophagy; Biomedical and Life Sciences; Biomedicine; Caspase-1; Cell Biology; Cell death; Cell viability; Dopamine; Dopamine D1 receptors; Embryos; Homeostasis; IL-1β; Inflammasomes; Inflammation; Localization; Neurobiology; Neurodegeneration; Neurodegenerative diseases; Neurosciences; Original Research; Phagosomes; Pyrin protein; Pyroptosis; Signal transduction; Therapeutic applications; Therapeutic targets; Zinc
• ISSN: 0272-4340; 1573-6830
• DOI: 10.1007/s10571-023-01367-z

Neuroinflammation is an early event during the pathogenesis of neurodegenerative disorders. Most studies focus on how the factors derived from pathogens or tissue damage activate the inflammation-pyroptosis cell death pathway. It is unclear whether endogenous neurotransmitters could induce inflammatory responses in neurons. Our previous reports have shown that dopamine-induced elevation of intracellular Zn 2+ concentration via the D1-like receptor (D1R) is a prerequisite for autophagy and cell death in primary cultured rat embryonic neurons. Here we further examined that this D1R-Zn 2+ signaling initiates the transient inflammatory response leading to cell death in cultured cortical neurons. Pretreating the cultured neurons with Zn 2+ chelator and inhibitors against inflammation could enhance the cell viability in neurons treated with dopamine and dihydrexidine, an agonist of D1R. Both dopamine and dihydrexidine greatly enhanced inflammasome formation; a Zn 2+ chelator, N,N,N′,N′-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine, suppressed this increment. Dopamine and dihydrexidine increased the expression levels of NOD-like receptor pyrin domain-containing protein 3 and enhanced the maturation of caspase-1, gasdermin D, and IL-1β; these changes were all Zn 2+ -dependent. Dopamine treatment did not recruit the N-terminal of the gasdermin D to the plasma membrane but enhanced its localization to the autophagosomes. Pretreating the neurons with IL-1β could increase the viability of neurons challenged with dopamine. These results demonstrate a novel D1R-Zn 2+ signaling cascade activating neuroinflammation and cell death. Therefore, maintaining a balance between dopamine homeostasis and inflammatory responses is an important therapeutic target for neurodegeneration. Graphical Abstract Dopamine elicits transient inflammatory responses in cultured cortical neurons via the D1R−Zn 2+ signaling pathway. Dopamine elevates [Zn 2+ ] i to induce the formation of inflammasomes, which activates caspase-1, resulting in the maturation of IL-1β and gasdermin D (GSDMD). Therefore, the homeostasis of dopamine and Zn 2+ are critical therapeutic targets for inflammation-derived neurodegeneration.