title: The sulfonylurea receptor 1 (Sur1)-transient receptor potential melastatin 4 (Trpm4) channel.
abstract: The sulfonylurea receptor 1 (Sur1)-NC(Ca-ATP) channel plays a central role in necrotic cell death in central nervous system (CNS) injury, including ischemic stroke, and traumatic brain and spinal cord injury. Here, we show that Sur1-NC(Ca-ATP) channels are formed by co-assembly of Sur1 and transient receptor potential melastatin 4 (Trpm4). Co-expression of Sur1 and Trpm4 yielded Sur1-Trpm4 heteromers, as shown in experiments with Förster resonance energy transfer (FRET) and co-immunoprecipitation. Co-expression of Sur1 and Trpm4 also yielded functional Sur1-Trpm4 channels with biophysical properties of Trpm4 and pharmacological properties of Sur1. Co-assembly with Sur1 doubled the affinity of Trpm4 for calmodulin and doubled its sensitivity to intracellular calcium. Experiments with FRET and co-immunoprecipitation showed de novo appearance of Sur1-Trpm4 heteromers after spinal cord injury in rats. Our findings depart from the long-held view of an exclusive association between Sur1 and K(ATP) channels and reveal an unexpected molecular partnership with far-ranging implications for CNS injury.
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Seung Kyoon
authors.initials: SK
authors.lastname: Woo
authors.forename: Min Seong
authors.initials: MS
authors.lastname: Kwon
authors.forename: Alexander
authors.initials: A
authors.lastname: Ivanov
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Gerzanich
authors.forename: J Marc
authors.initials: JM
authors.lastname: Simard
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D003981:Diazoxide / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer; D005905:Glyburide / Q000494:pharmacology; D006031:Glycosylation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D051381:Rats; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000473:pathology; D064233:Sulfonylurea Receptors; D050053:TRPM Cation Channels / Q000378:metabolism*
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; C577508:Abcc8 protein, mouse; C577509:Abcc8 protein, rat; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D011994:Recombinant Proteins; D064233:Sulfonylurea Receptors; D050053:TRPM Cation Channels; C476766:TRPM4 protein, mouse; C500239:TRPM4 protein, rat; D003981:Diazoxide; D005905:Glyburide