title: Sur1-Trpm4 Cation Channel Expression in Human Cerebral Infarcts.
abstract: The nonselective monovalent cation channel transient receptor potential melastatin 4 (Trpm4) is transcriptionally upregulated in neural and vascular cells in animal models of brain infarction. It associates with sulfonylurea receptor 1 (Sur1) to form Sur1-Trpm4 channels, which have critical roles in cytotoxic edema, cell death, blood-brain barrier breakdown, and vasogenic edema. We examined Trpm4 expression in postmortem brain specimens from 15 patients who died within the first 31 days of the onset of focal cerebral ischemia. We found increased Trpm4 protein expression in all cases using immunohistochemistry; transcriptional upregulation was confirmed using in situ hybridization of Trpm4 messenger RNA. Transient receptor potential melastatin 4 colocalized and coassociated with Sur1 within ischemic endothelial cells and neurons. Coexpression of Sur1 and Trpm4 in necrotic endothelial cells was also associated with vasogenic edema indicated by upregulated perivascular tumor necrosis factor, extravasation of serum immunoglobulin G, and associated inflammation. Upregulated Trpm4 protein was present up to 1 month after the onset of cerebral ischemia. In a rat model of middle cerebral artery occlusion stroke, pharmacologic channel blockade by glibenclamide, a selective inhibitor of sulfonylurea receptor, mitigated perivascular tumor necrosis factor labeling. Thus, upregulated Sur1-Trpm4 channels and associated blood-brain barrier disruption and cerebral edema suggest that pharmacologic targeting of this channel may represent a promising therapeutic strategy for the clinical management of patients with cerebral ischemia.
authors.affiliation: From the Departments of Pathology (RIM, RJC, JMS), Neurosurgery (SI, NT, MSK, VG, JMS), Neurology (BMF), and Physiology (JMS), University of Maryland School of Medicine, Baltimore, Maryland; and the Department of Molecular Biology and Genetics (CT), Izmir Institute of Technology, Izmir, Turkey.
authors.forename: Rupal I
authors.initials: RI
authors.lastname: Mehta
authors.forename: Cigdem
authors.initials: C
authors.lastname: Tosun
authors.forename: Svetlana
authors.initials: S
authors.lastname: Ivanova
authors.forename: Natalia
authors.initials: N
authors.lastname: Tsymbalyuk
authors.forename: Bolanle M
authors.initials: BM
authors.lastname: Famakin
authors.forename: Min Seong
authors.initials: MS
authors.lastname: Kwon
authors.forename: Rudy J
authors.initials: RJ
authors.lastname: Castellani
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Gerzanich
authors.forename: J Marc
authors.initials: JM
authors.lastname: Simard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002544:Cerebral Infarction / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D064233:Sulfonylurea Receptors / Q000096:biosynthesis*; D050053:TRPM Cation Channels / Q000096:biosynthesis*; D015854:Up-Regulation
chemical_list: C577507:ABCC8 protein, human; D064233:Sulfonylurea Receptors; D050053:TRPM Cation Channels; C437888:TRPM4 protein, human