Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 5, Pages 3655-3667Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.428219
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Funding
- National Institutes of Health [NS060801, NS061808, HL082517, NS061934, NS072501]
- Department of Veterans Affairs (Baltimore, MD)
- Department of the Army [W81XWH 1010898]
- Christopher and Dana Reeve Foundation
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The sulfonylurea receptor 1 (Sur1)-NCCa-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-NCCa-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 Forster 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.
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