Homer1 Scaffold Proteins Govern Ca2+ Dynamics in Normal and Reactive Astrocytes.
Détails
ID Serval
serval:BIB_B36CA8DF891F
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Homer1 Scaffold Proteins Govern Ca2+ Dynamics in Normal and Reactive Astrocytes.
Périodique
Cerebral cortex (New York, N.Y. : 1991)
ISSN
1460-2199 (Electronic)
ISSN-L
1047-3211
Statut éditorial
Publié
Date de publication
01/03/2017
Peer-reviewed
Oui
Volume
27
Numéro
3
Pages
2365-2384
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
In astrocytes, the intracellular calcium (Ca2+) signaling mediated by activation of metabotropic glutamate receptor 5 (mGlu5) is crucially involved in the modulation of many aspects of brain physiology, including gliotransmission. Here, we find that the mGlu5-mediated Ca2+ signaling leading to release of glutamate is governed by mGlu5 interaction with Homer1 scaffolding proteins. We show that the long splice variants Homer1b/c are expressed in astrocytic processes, where they cluster with mGlu5 at sites displaying intense local Ca2+ activity. We show that the structural and functional significance of the Homer1b/c-mGlu5 interaction is to relocate endoplasmic reticulum (ER) to the proximity of the plasma membrane and to optimize Ca2+ signaling and glutamate release. We also show that in reactive astrocytes the short dominant-negative splice variant Homer1a is upregulated. Homer1a, by precluding the mGlu5-ER interaction decreases the intensity of Ca2+ signaling thus limiting the intensity and the duration of glutamate release by astrocytes. Hindering upregulation of Homer1a with a local injection of short interfering RNA in vivo restores mGlu5-mediated Ca2+ signaling and glutamate release and sensitizes astrocytes to apoptosis. We propose that Homer1a may represent one of the cellular mechanisms by which inflammatory astrocytic reactions are beneficial for limiting brain injury.
Mots-clé
Animals, Astrocytes/metabolism, Brain Ischemia/metabolism, Calcium/metabolism, Cations, Divalent/metabolism, Cells, Cultured, Cerebral Cortex/growth & development, Cerebral Cortex/metabolism, Endoplasmic Reticulum/metabolism, Glial Fibrillary Acidic Protein/genetics, Glial Fibrillary Acidic Protein/metabolism, Glutamic Acid/metabolism, Green Fluorescent Proteins/genetics, Green Fluorescent Proteins/metabolism, Homer Scaffolding Proteins/antagonists & inhibitors, Homer Scaffolding Proteins/genetics, Homer Scaffolding Proteins/metabolism, Humans, Infant, Newborn, Male, Mice, Transgenic, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5/metabolism, Receptors, Metabotropic Glutamate/metabolism, Tissue Culture Techniques
Pubmed
Open Access
Oui
Création de la notice
03/05/2016 18:05
Dernière modification de la notice
20/08/2019 16:21