title: Homer1 Scaffold Proteins Govern Ca2+ Dynamics in Normal and Reactive Astrocytes.
abstract: 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.
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, CH1005 Lausanne, Switzerland.|Stroke Laboratory, Neurology Service, Department of Clinical Neurosciences, University Hospital Centre and University of Lausanne, CH-1011 Lausanne, Switzerland.
authors.forename: Lara
authors.initials: L
authors.lastname: Buscemi
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, CH1005 Lausanne, Switzerland.|Division of Neonatology, Department of Paediatrics and Paediatric Surgery, University Hospital Centre and University of Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Ginet
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, CH1005Lausanne, Switzerland.
authors.forename: Jan
authors.initials: J
authors.lastname: Lopatar
authors.affiliation: Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia.|Department of Neurobiology, Center for Glial Biology in Medicine, Civitan International Research Center, Atomic Force Microscopy and Nanotechnology Laboratories, and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Vedrana
authors.initials: V
authors.lastname: Montana
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, CH1005Lausanne, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Pucci
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, CH1005 Lausanne, Switzerland.|Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Spagnuolo
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, CH1005Lausanne, Switzerland.
authors.forename: Tamara
authors.initials: T
authors.lastname: Zehnder
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, Civitan International Research Center, Atomic Force Microscopy and Nanotechnology Laboratories, and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Grubišic
authors.affiliation: Division of Neonatology, Department of Paediatrics and Paediatric Surgery, University Hospital Centre and University of Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Anita
authors.initials: A
authors.lastname: Truttman
authors.affiliation: CNR Institute of Neuroscience and Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Sala
authors.affiliation: Stroke Laboratory, Neurology Service, Department of Clinical Neurosciences, University Hospital Centre and University of Lausanne, CH-1011 Lausanne, Switzerland.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Hirt
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, Civitan International Research Center, Atomic Force Microscopy and Nanotechnology Laboratories, and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Parpura
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, CH1005 Lausanne, Switzerland.|Division of Neonatology, Department of Paediatrics and Paediatric Surgery, University Hospital Centre and University of Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Puyal
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, CH1005Lausanne, Switzerland.
authors.forename: Paola
authors.initials: P
authors.lastname: Bezzi
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002413:Cations, Divalent / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D000072233:Homer Scaffolding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008822:Mice, Transgenic; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D002413:Cations, Divalent; D005904:Glial Fibrillary Acidic Protein; C000606614:HOMER1 protein, human; D000072233:Homer Scaffolding Proteins; C000606623:Homer1 protein, mouse; C000606624:Homer1 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C485184:enhanced green fluorescent protein; C104077:metabotropic glutamate receptor type 1; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D002118:Calcium
keywords: Homer; astrocytes; intracellular Ca2+; mGlu5; neuroinflammation