Dysregulation of Ca2+ signaling in astrocytes from mice lacking amyloid precursor protein
| Autor: | Cristina I. Linde, Sergey G. Baryshnikov, Amparo Mazzocco-Spezzia, Vera A. Golovina |
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| Rok vydání: | 2011 |
| Předmět: |
ORAI1 Protein
Physiology Ratón chemistry.chemical_element Mice Transgenic Calcium Amyloid beta-Protein Precursor Mice mental disorders medicine Amyloid precursor protein Animals Homeostasis Calcium Signaling Stromal Interaction Molecule 1 RNA Small Interfering Nervous System Cell Biology Cells Cultured Fluorescent Dyes TRPC Cation Channels Mice Knockout Membrane Glycoproteins biology ORAI1 Cell Biology Mice Inbred C57BL medicine.anatomical_structure Biochemistry chemistry Astrocytes biology.protein Neuroglia Calcium Channels Signal transduction Fura-2 Ca2 signaling Astrocyte |
| Zdroj: | American journal of physiology. Cell physiology. 300(6) |
| ISSN: | 1522-1563 |
| Popis: | The relationship between altered metabolism of the amyloid-β precursor protein (APP) and Alzheimer's disease is well established but the physiological roles of APP still remain unclear. Here, we studied Ca2+ signaling in primary cultured and freshly dissociated cortical astrocytes from APP knockout (KO) mice and from Tg5469 mice overproducing by five- to sixfold wild-type APP. Resting cytosolic Ca2+ (measured with fura-2) was not altered in cultured astrocytes from APP KO mice. The stored Ca2+ evaluated by measuring peak amplitude of cyclopiazonic acid [CPA, endoplasmic reticulum (ER) Ca2+ ATPase inhibitor]-induced Ca2+ transients in Ca2+-free medium was significantly smaller in APP KO astrocytes than in wild-type cells. Store-operated Ca2+ entry (SOCE) activated by ER Ca2+ store depletion with CPA was also greatly reduced in APP KO astrocytes. This reflected a downregulated expression in APP KO astrocytes of TRPC1 (C-type transient receptor potential) and Orai1 proteins, essential components of store-operated channels (SOCs). Indeed, silencer RNA (siRNA) knockdown of Orai1 protein expression in wild-type astrocytes significantly attenuated SOCE. SOCE was also essentially reduced in freshly dissociated APP KO astrocytes. Importantly, knockdown of APP with siRNA in cultured wild-type astrocytes markedly attenuated ATP- and CPA-induced ER Ca2+ release and extracellular Ca2+ influx. The latter correlated with downregulation of TRPC1. Overproduction of APP in Tg5469 mice did not alter, however, the stored Ca2+ level, SOCE, and expression of TRPC1/4/5 in cultured astrocytes from these mice. The data demonstrate that the functional role of APP in astrocytes involves the regulation of TRPC1/Orai1-encoded SOCs critical for Ca2+ signaling. |
| Databáze: | OpenAIRE |
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