Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Dopaminergic neurotoxicants cause biphasic inhibition of purinergic calcium signaling in astrocytes.

Authors: Streifel, Karin M; Gonzales, Albert L; De Miranda, Briana; Mouneimne, Rola; Earley, Scott; Tjalkens, Ronald

Published In PLoS One, (2014)

Abstract: Dopaminergic nuclei in the basal ganglia are highly sensitive to damage from oxidative stress, inflammation, and environmental neurotoxins. Disruption of adenosine triphosphate (ATP)-dependent calcium (Ca2+) transients in astrocytes may represent an important target of such stressors that contributes to neuronal injury by disrupting critical Ca2+-dependent trophic functions. We therefore postulated that plasma membrane cation channels might be a common site of inhibition by structurally distinct cationic neurotoxicants that could modulate ATP-induced Ca2+ signals in astrocytes. To test this, we examined the capacity of two dopaminergic neurotoxicants to alter ATP-dependent Ca2+ waves and transients in primary murine striatal astrocytes: MPP+, the active metabolite of 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and 6-hydroxydopamine (6-OHDA). Both compounds acutely decreased ATP-induced Ca2+ transients and waves in astrocytes and blocked OAG-induced Ca2+ influx at micromolar concentrations, suggesting the transient receptor potential channel, TRPC3, as an acute target. MPP+ inhibited 1-oleoyl-2-acetyl-sn-glycerol (OAG)-induced Ca2+ transients similarly to the TRPC3 antagonist, pyrazole-3, whereas 6-OHDA only partly suppressed OAG-induced transients. RNAi directed against TRPC3 inhibited the ATP-induced transient as well as entry of extracellular Ca2+, which was augmented by MPP+. Whole-cell patch clamp experiments in primary astrocytes and TRPC3-overexpressing cells demonstrated that acute application of MPP+ completely blocked OAG-induced TRPC3 currents, whereas 6-OHDA only partially inhibited OAG currents. These findings indicate that MPP+ and 6-OHDA inhibit ATP-induced Ca2+ signals in astrocytes in part by interfering with purinergic receptor mediated activation of TRPC3, suggesting a novel pathway in glia that could contribute to neurotoxic injury.

PubMed ID: 25365260 Exiting the NIEHS site

MeSH Terms: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology; Adenosine Triphosphate/metabolism; Animals; Astrocytes/drug effects*; Astrocytes/metabolism*; Calcium Signaling/drug effects*; Calcium/metabolism; Cell Line; Corpus Striatum/cytology; Corpus Striatum/drug effects; Corpus Striatum/metabolism; Dopamine Agents/pharmacology*; Humans; Mice; Neurotoxins/pharmacology*; Oxidopamine/pharmacology; Purinergic Agents/pharmacology*; Receptors, G-Protein-Coupled/metabolism; TRPC Cation Channels/metabolism

Back
to Top