title: Manganese inhibits ATP-induced calcium entry through the transient receptor potential channel TRPC3 in astrocytes.
abstract: Chronic exposure to elevated levels of manganese (Mn(2+)) causes neuronal injury and inflammatory activation of glia. Astrocytes selectively accumulate Mn(2+), which inhibits mitochondrial respiration and increases production of reactive oxygen species. We previously reported that sub-acute exposure to low micromolar levels of Mn(2+) in primary astrocytes inhibited ATP-induced calcium (Ca(2+)) signaling, associated with decreased levels of endoplasmic reticulum Ca(2+) and increased mitochondrial Ca(2+) loads. In the present studies, we postulated that the mechanism underlying the capacity of Mn(2+) to inhibit these purinergic signals in astrocytes could be due to competition with Ca(2+) for entry through a plasma membrane channel. These data demonstrate that acutely applied Mn(2+) rapidly inhibited ATP-induced Ca(2+) waves and transients in primary striatal astrocytes. Mn(2+) also decreased influx of extracellular Ca(2+) induced by 1-oleoyl-2-acetyl-sn-glycerol (OAG), a direct activator of the transient receptor potential channel, TRPC3. The TRPC3 inhibitor, pyrazole-3, prevented ATP- and OAG-dependent transport of Mn(2+) from extracellular stores, demonstrated by a dramatic reduction in the rate of fluorescence quenching of Fura-2. These data indicate that Mn(2+) can acutely inhibit ATP-dependent Ca(2+) signaling in astrocytes by blocking Ca(2+) entry through the receptor-operated cation channel, TRPC3. Loss of normal astrocytic responses to purinergic signals due to accumulation of Mn(2+) could therefore comprise critical homeostatic functions necessary for metabolic and trophic support of neurons.
authors.affiliation: Center for Environmental Medicine, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523-1680, United States.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Streifel
authors.forename: James
authors.initials: J
authors.lastname: Miller
authors.forename: Rola
authors.initials: R
authors.lastname: Mouneimne
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Tjalkens
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002450:Cell Communication; D002478:Cells, Cultured; D004075:Diglycerides / Q000494:pharmacology; D008345:Manganese / Q000378:metabolism* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D011720:Pyrazoles / Q000494:pharmacology; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors
chemical_list: C520323:1-oleoyl-2-acetoyl-sn-glycerol; D002121:Calcium Channel Blockers; D004075:Diglycerides; D011720:Pyrazoles; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D008345:Manganese; D000255:Adenosine Triphosphate; D002118:Calcium