Dopaminergic neurotoxicants cause biphasic inhibition of purinergic calcium signaling in astrocytes

Authors

• Karin M. Streifel, Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado, United States of America.
• Albert L. Gonzales, Vascular Physiology Research Group, Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
• Briana De Miranda, Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado, United States of America.
• Rola Mouneimne, Department of Veterinary Integrative Biosciences, Texas A & M University, College Station, Texas, United States of America.
• Scott Earley, Vascular Physiology Research Group, Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
• Ronald Tjalkens, Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado, United States of America.

Document Type

Article

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.

Medical Subject Headings

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

Publication Date

1-1-2014

Publication Title

PloS one

E-ISSN

1932-6203

Volume

9

Issue

11

First Page

e110996

PubMed ID

25365260

Digital Object Identifier (DOI)

10.1371/journal.pone.0110996

Recommended Citation

Streifel, Karin M.; Gonzales, Albert L.; De Miranda, Briana; Mouneimne, Rola; Earley, Scott; and Tjalkens, Ronald, "Dopaminergic neurotoxicants cause biphasic inhibition of purinergic calcium signaling in astrocytes" (2014). Translational Neuroscience. 2520.
https://scholar.barrowneuro.org/neurobiology/2520