The sulfonylurea receptor 1 (Sur1)-transient receptor potential melastatin 4 (Trpm4) channel

J Biol Chem. 2013 Feb 1;288(5):3655-67. doi: 10.1074/jbc.M112.428219. Epub 2012 Dec 19.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • COS Cells
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Chlorocebus aethiops
  • Diazoxide / pharmacology
  • Fluorescence Resonance Energy Transfer
  • Glyburide / pharmacology
  • Glycosylation / drug effects
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • Mice
  • Potassium Channels, Inwardly Rectifying / antagonists & inhibitors
  • Potassium Channels, Inwardly Rectifying / metabolism*
  • Protein Binding / drug effects
  • Protein Multimerization / drug effects
  • Rats
  • Receptors, Drug / antagonists & inhibitors
  • Receptors, Drug / metabolism*
  • Recombinant Proteins / metabolism
  • Spinal Cord Injuries / metabolism
  • Spinal Cord Injuries / pathology
  • Sulfonylurea Receptors
  • TRPM Cation Channels / metabolism*


  • ABCC8 protein, human
  • ATP-Binding Cassette Transporters
  • Abcc8 protein, mouse
  • Abcc8 protein, rat
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Drug
  • Recombinant Proteins
  • Sulfonylurea Receptors
  • TRPM Cation Channels
  • TRPM4 protein, mouse
  • TRPM4 protein, rat
  • Diazoxide
  • Glyburide