Abstract
Sulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily, encoded by Abcc8, and is recognized as a key mediator of central nervous system (CNS) cellular swelling via the transient receptor potential melastatin 4 (TRPM4) channel. Discovered approximately 20 years ago, this channel is normally absent in the CNS but is transcriptionally upregulated after CNS injury. A comprehensive review on the pathophysiology and role of SUR1 in the CNS was published in 2012. Since then, the breadth and depth of understanding of the involvement of this channel in secondary injury has undergone exponential growth: SUR1-TRPM4 inhibition has been shown to decrease cerebral edema and hemorrhage progression in multiple preclinical models as well as in early clinical studies across a range of CNS diseases including ischemic stroke, traumatic brain injury, cardiac arrest, subarachnoid hemorrhage, spinal cord injury, intracerebral hemorrhage, multiple sclerosis, encephalitis, neuromalignancies, pain, liver failure, status epilepticus, retinopathies and HIV-associated neurocognitive disorder. Given these substantial developments, combined with the timeliness of ongoing clinical trials of SUR1 inhibition, now, another decade later, we review advances pertaining to SUR1-TRPM4 pathobiology in this spectrum of CNS disease—providing an overview of the journey from patch-clamp experiments to phase III trials.
Highlights
Sulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)binding cassette (ABC) protein superfamily, which encompasses a large group of membrane proteins that assist in and regulate the transport of ions and molecules across lipid bilayers [1,2]
Both SUR1-Kir6.2 and SUR1-transient receptor potential melastatin 4 (TRPM4) channels are both regulated by SUR1, these two associations have opposite functional effects in central nervous system (CNS) injury: KATP channel opening leads to potassium efflux and hyperpolarization of cells [2,6,11,63,64], whereas SUR1-TRPM4 channel opening leads to influx of monovalent cations, resulting in depolarization of the cell, cytotoxic edema, blebbing, and oncotic cell death (Section 2.2) [6,7,8,11,65]
In addition to its action on the closed/open state of SUR1-TRPM4, glibenclamide may decrease surface expression of channel complexes; this has been noted for KATP channels, apparently due to abnormal trafficking induced by the drug [80]
Summary
Sulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)binding cassette (ABC) protein superfamily, which encompasses a large group of membrane proteins that assist in and regulate the transport of ions and molecules across lipid bilayers [1,2]. SUR1 co-associates with the pore-forming subunit, KIR6.2/Kcnj, an ATPsensitive potassium channel, to form KATP channels, whose role has historically been extensively studied in pancreatic β cells and diabetes mellitus [2,61,62] Both SUR1-Kir6.2 and SUR1-TRPM4 channels are both regulated by SUR1, these two associations have opposite functional effects in CNS injury: KATP channel opening leads to potassium efflux and hyperpolarization of cells [2,6,11,63,64], whereas SUR1-TRPM4 channel opening leads to influx of monovalent cations, resulting in depolarization of the cell, cytotoxic edema, blebbing, and oncotic cell death (Section 2.2) [6,7,8,11,65]. SUR1 can associate with the inwardly rectifying potassium channel, Kir6.1/Kcnj8 [66,67], but this combination has not been reported in nature
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