title: Identification of a molecular target for glutamate regulation of astrocyte water permeability.
abstract: Astrocytes play a key role for maintenance of brain water homeostasis, but little is known about mechanisms of short-term regulation of astrocyte water permeability. Here, we report that glutamate increases astrocyte water permeability and that the molecular target for this effect is the aquaporin-4 (AQP4) serine 111 residue, which is in a strategic position for control of the water channel gating. The glutamate effect involves activation of group I metabotropic glutamate receptors (mGluR), intracellular calcium release, and activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and nitric oxide synthase (NOS). The physiological impact of our results is underlined by the finding that mGluR activation increases the rate of hypoosmotic tissue swelling in acute rat hippocampal slices. Cerebral ischemia is associated with an excessive release of glutamate, and in postischemic cerebral edema ablation of AQP4 attenuates the degree of damage. Thus, we have identified AQP4 as the molecular target for drugs that may attenuate the development of brain edema.
authors.affiliation: Department of Woman and Child Health, Karolinska Institutet, Nordic Centre of Excellence for Research in Water Imbalance Related Disorders, Stockholm, Sweden.
authors.forename: Eli
authors.initials: E
authors.lastname: Gunnarson
authors.forename: Marina
authors.initials: M
authors.lastname: Zelenina
authors.forename: Gustav
authors.initials: G
authors.lastname: Axehult
authors.forename: Yutong
authors.initials: Y
authors.lastname: Song
authors.forename: Alexander
authors.initials: A
authors.lastname: Bondar
authors.forename: Patrik
authors.initials: P
authors.lastname: Krieger
authors.forename: Hjalmar
authors.initials: H
authors.lastname: Brismar
authors.forename: Sergey
authors.initials: S
authors.lastname: Zelenin
authors.forename: Anita
authors.initials: A
authors.lastname: Aperia
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051401:Aquaporin 4 / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D014867:Water / Q000378:metabolism*; D000096926:Benzenesulfonamides
chemical_list: D051401:Aquaporin 4; D001596:Benzylamines; D002118:Calcium; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018698:Glutamic Acid; D049452:Green Fluorescent Proteins; D008734:Methoxyhydroxyphenylglycol; D016202:N-Methylaspartate; D018094:Receptors, Metabotropic Glutamate; D012694:Serine; D013449:Sulfonamides; D014867:Water; C496032:Aqp4 protein, rat; C104077:metabotropic glutamate receptor type 1; C072105:KN 93; D000096926:Benzenesulfonamides; C010117:3,4-dihydroxyphenylglycol