Homer1 Scaffold Proteins Govern Ca2+ Dynamics in Normal and Reactive Astrocytes
| Autor: | Lara Buscemi, Paola Spagnuolo, Vedrana Montana, Tamara Zehnder, Paola Bezzi, Vladimir Grubišić, Vanessa Ginet, Jan Lopatar, Anita Truttman, Vladimir Parpura, Julien Puyal, Luca Pucci, Carlo Sala, Lorenz Hirt |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Scaffold protein Cations Divalent Receptor Metabotropic Glutamate 5 Cognitive Neuroscience Green Fluorescent Proteins Glutamic Acid Mice Transgenic Endoplasmic Reticulum Receptors Metabotropic Glutamate Calcium in biology Brain Ischemia Rats Sprague-Dawley Tissue Culture Techniques 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Homer Scaffolding Proteins Downregulation and upregulation Glial Fibrillary Acidic Protein Animals Humans Cells Cultured Neuroinflammation Cerebral Cortex Chemistry Metabotropic glutamate receptor 5 Endoplasmic reticulum Infant Newborn Glutamate receptor Original Articles Glutamic acid Cell biology 030104 developmental biology Astrocytes Calcium 030217 neurology & neurosurgery |
| Zdroj: | Cerebral Cortex. 27:2365-2384 |
| ISSN: | 1460-2199 1047-3211 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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