Sulfonylurea receptor 1 and 2 (SUR1/SUR2)

The ATP-sensitive potassium (KATP) channel is a hetero-octameric complex consisting of four pore-forming subunits (Kir6.1 or Kir6.2) and four regulatory sulfonylurea receptor subunits (SUR1 or SUR2) (Nichols, 2006). SUR1, encoded by the ABCC8 gene, is primarily expressed in pancreatic beta cells and neurons, where it plays a critical role in regulating insulin secretion and neuronal excitability (Aguilar-Bryan and Bryan, 1999). SUR2, encoded by the ABCC9 gene, exists as two major isoforms: SUR2A (predominant in cardiac muscle) and SUR2B (predominant in vascular smooth muscle), which modulate cardiac contractility and vascular tone (Seino and Miki, 2003). These subunits act as metabolic sensors by binding intracellular ATP and ADP, thereby coupling the cell's energy status to its electrical activity (Ashcroft, 2005). Pharmacologically, SUR subunits are the primary targets for several classes of drugs; sulfonylureas and glinides bind to SUR1 to inhibit KATP channels, leading to membrane depolarization and insulin release, making them a mainstay for treating type 2 diabetes (Sola et al., 2015). Conversely, potassium channel openers like diazoxide and nicorandil bind to SUR subunits to activate the channels, causing hyperpolarization and vasodilation, which is useful in treating conditions like hyperinsulinism and angina (Hibino et al., 2010). Mutations in ABCC8 and ABCC9 are linked to various channelopathies, including congenital hyperinsulinism, neonatal diabetes, and Cantu syndrome (Ashcroft et al., 2017). Additionally, the SUR1-TRPM4 channel complex has emerged as a target for reducing cerebral edema following stroke or traumatic brain injury (Simard et al., 2006).

Other names

ABCC8ABCC9ATP-binding cassette sub-family C member 8ATP-binding cassette sub-family C member 9KATP channel regulatory subunitsSulfonylurea receptor

Sulfonylureas and glinides act as channel blockers by binding to the SUR subunits (primarily SUR1), leading to channel closure, membrane depolarization, and stimulation of insulin secretion. Potassium channel openers (KCOs) act as channel activators by binding to SUR subunits (SUR1, SUR2A, or SUR2B), promoting channel opening and membrane hyperpolarization, which results in vasodilation or reduced excitability.