Sulfonylurea receptor 1-Transient receptor potential melastatin 4 ion channel complex (SUR1-TRPM4)

The Sulfonylurea receptor 1-Transient receptor potential melastatin 4 (SUR1-TRPM4) ion channel complex is a heteromeric structure that plays a pivotal role in the development of cerebral edema following acute central nervous system (CNS) injury. This complex is unique because it is not constitutively expressed in healthy CNS tissues but is de novo upregulated in neurons, astrocytes, and capillary endothelial cells following insults such as ischemic stroke, traumatic brain injury, or subarachnoid hemorrhage (Simard et al., 2006, Nature Medicine; Woo et al., 2013, J Cereb Blood Flow Metab). The channel is composed of the regulatory subunit SUR1 (encoded by ABCC8) and the pore-forming subunit TRPM4; it is activated by a decrease in intracellular ATP and an increase in intracellular calcium (Simard et al., 2007, Biochim Biophys Acta). Once open, the channel allows a non-selective influx of monovalent cations, which leads to water influx, oncotic cell swelling, and eventually, the breakdown of the blood-brain barrier and catastrophic tissue damage (Kurland et al., 2013, Transl Stroke Res). Because of its specific expression in injured tissue, it has become a high-interest therapeutic target. The sulfonylurea drug glibenclamide (glyburide) acts as a potent inhibitor of this complex, and clinical trials have investigated its efficacy in reducing brain swelling and improving survival in patients with large territory strokes (Sheth et al., 2016, Lancet Neurol).

Other names

SUR1-TRPM4 channelNCCa-ATP channelNon-selective cation channel activated by calcium and inhibited by ATPABCC8-TRPM4 complex

Inhibition of the SUR1 regulatory subunit to prevent the opening of the TRPM4 pore, thereby blocking the influx of monovalent cations and preventing oncotic cell swelling.