Increased expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in reactive astrocytes following ischemia
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25042871
DOI
10.1002/glia.22721
Knihovny.cz E-resources
- Keywords
- HCN channels, ZD7288, astrocytes, cortex, focal and global cerebral ischemia, hippocampus,
- MeSH
- Cyclic AMP pharmacology MeSH
- Astrocytes drug effects metabolism MeSH
- Glial Fibrillary Acidic Protein genetics metabolism MeSH
- Ischemia pathology MeSH
- Cyclic Nucleotide-Gated Cation Channels genetics metabolism MeSH
- Rats MeSH
- Membrane Potentials drug effects physiology MeSH
- Disease Models, Animal MeSH
- Brain cytology MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- Neurons drug effects metabolism MeSH
- Rats, Wistar MeSH
- Nerve Tissue Proteins genetics metabolism MeSH
- Pyrimidines pharmacology MeSH
- Gene Expression Regulation drug effects physiology MeSH
- Sodium metabolism MeSH
- In Vitro Techniques MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Cyclic AMP MeSH
- Glial Fibrillary Acidic Protein MeSH
- ICI D2788 MeSH Browser
- Cyclic Nucleotide-Gated Cation Channels MeSH
- Nerve Tissue Proteins MeSH
- Pyrimidines MeSH
- Sodium MeSH
Astrocytes respond to ischemic brain injury by proliferation, the increased expression of intermediate filaments and hypertrophy, which results in glial scar formation. In addition, they alter the expression of ion channels, receptors and transporters that maintain ionic/neurotransmitter homeostasis. Here, we aimed to demonstrate the expression of Hcn1-4 genes encoding hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in reactive astrocytes following focal cerebral ischemia (FCI) or global cerebral ischemia (GCI) and to characterize their functional properties. A permanent occlusion of the middle cerebral artery (MCAo) was employed to induce FCI in adult GFAP/EGFP mice, while GCI was induced by transient bilateral common carotid artery occlusion combined with hypoxia in adult rats. Using FACS, we isolated astrocytes from non-injured or ischemic brains and performed gene expression profiling using single-cell RT-qPCR. We showed that 2 weeks after ischemia reactive astrocytes express high levels of Hcn1-4 transcripts, while immunohistochemical analyses confirmed the presence of HCN1-3 channels in reactive astrocytes 5 weeks after ischemia. Electrophysiological recordings revealed that post-ischemic astrocytes are significantly depolarized, and compared with astrocytes from non-injured brains, they display large hyperpolarization-activated inward currents, the density of which increased 2-3-fold in response to ischemia. Their activation was facilitated by cAMP and their amplitudes were decreased by ZD7288 or low extracellular Na(+) concentration, suggesting that they may belong to the family of HCN channels. Collectively, our results demonstrate that regardless of the type of ischemic injury, reactive astrocytes express HCN channels, which could therefore be an important therapeutic target in poststroke therapy.
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