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Pathophysiological Significance of Canonical Transient Receptor Potential (TRPC) Subfamily in Astrocyte Activation
- Source :
- YAKUGAKU ZASSHI. 132:587-593
- Publication Year :
- 2012
- Publisher :
- Pharmaceutical Society of Japan, 2012.
-
Abstract
- Astrocytes, the most abundant cells in the central nervous system (CNS), play diverse roles in the regulation of neuronal activity, vascular function and gliotransmitter release. In neurodegenerative diseases, pathologically activated astrocytes show astrogliosis, which is clinically characterized by an abnormal cell morphology and excessive astrocyte proliferation. Thrombin, a crucial factor for brain injury after intracerebral hemorrhage, activates astrocytic Ca2+ signaling through a specific subtype of the thrombin receptor, termed the proteinase-activated receptor (PAR). In this study, we demonstrate a novel pathophysiological role for transient receptor potential canonical 3 (TRPC3) Ca2+-permeable nonselective cation channels in thrombin-activated astrocytes. In 1321N1 human astrocytoma cells and cultured rat cortical astrocytes, thrombin induced heterogeneous Ca2+ responses with asynchronous repetitive peaks. These oscillations were found to be the result of repetitive Ca2+ release from intracellular stores followed by replenishment of the stores with Ca2+ from the extracellular region. The oscillations occurred without a direct [Ca2+]i increase and were inhibited by the selective TRPC3 inhibitor pyrazole-3. Pharmacological manipulation with BAPTA-AM, cyclopiazonic acid, 2-aminoethoxydiphenyl borate and pyrazole-3 indicated that Ca2+ mobilization through TRPC3 was involved in thrombin-induced changes in the morphology of astrocytes. Moreover, thrombin-induced upregulation of S100B, a marker of reactive astrocytes, at 20 h and increased astrocytic proliferation at 72 h were inhibited by Ca2+ signaling blockers and knockdown of TRPC3 with specific siRNA. Taken together, these results suggest that TRPC3 may constitute a new therapeutic target for brain injury after intracerebral hemorrhage.
- Subjects :
- Gliotransmitter
Pharmaceutical Science
S100 Calcium Binding Protein beta Subunit
Astrocytoma
Biology
Transient receptor potential channel
TRPC3
Theophylline
Thrombin receptor
medicine
Animals
Humans
Calcium Signaling
Molecular Targeted Therapy
Nerve Growth Factors
RNA, Small Interfering
Receptor
TRPC
Cell Proliferation
Cerebral Hemorrhage
TRPC Cation Channels
Pharmacology
S100 Proteins
Thrombin
medicine.disease
Rats
Cell biology
Astrogliosis
medicine.anatomical_structure
Astrocytes
Brain Injuries
Immunology
Pyrazoles
Calcium
Biomarkers
Astrocyte
Subjects
Details
- ISSN :
- 13475231 and 00316903
- Volume :
- 132
- Database :
- OpenAIRE
- Journal :
- YAKUGAKU ZASSHI
- Accession number :
- edsair.doi.dedup.....cc68a4c3a928686e31ce2b6a2e1423cd