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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)-transient receptor potential melastatin 4 (Trpm4) channel.

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1
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

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.

PMID:
23255597
PMCID:
PMC3561583
DOI:
10.1074/jbc.M112.428219
[Indexed for MEDLINE]
Free PMC Article

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