Sulfonylurea receptor 1 (SUR1) (SUR1)

The Sulfonylurea receptor 1 (SUR1), encoded by the ABCC8 gene, is a critical regulatory subunit of the ATP-sensitive potassium (K-ATP) channel [3, 5]. It belongs to the ATP-binding cassette (ABC) transporter superfamily but functions primarily as a metabolic sensor rather than a transporter [4, 11]. In pancreatic beta cells, SUR1 couples the cell's metabolic state (ATP/ADP ratio) to its electrical activity; high ATP levels lead to channel closure, membrane depolarization, and subsequent insulin release [1, 13]. This mechanism is essential for maintaining glucose homeostasis and is the primary pathway targeted by insulin secretagogues [2, 8]. SUR1 is a major therapeutic target for metabolic and neurological disorders [1, 10]. Gain-of-function mutations in ABCC8 cause neonatal diabetes, while loss-of-function mutations lead to congenital hyperinsulinism [3, 16]. Pharmacologically, sulfonylureas and meglitinides bind to SUR1 to stimulate insulin secretion in Type 2 diabetes, whereas diazoxide acts as an opener to treat hyperinsulinism [5, 7]. Beyond the pancreas, SUR1 is upregulated in the central nervous system following injury, such as stroke or trauma, where it associates with TRPM4 to form channels that contribute to cerebral edema and secondary tissue damage [9, 10]. Consequently, SUR1 inhibition is being investigated as a neuroprotective strategy to reduce brain swelling [5, 9].

Other names

ABCC8ATP-binding cassette sub-family C member 8ABC36HRINSPHHIMRP8ATP-sensitive potassium channel regulatory subunit SUR1

Drugs targeting SUR1 modulate the activity of ATP-sensitive potassium (K-ATP) channels [1, 4]. Sulfonylureas (e.g., glibenclamide) and meglitinides (e.g., repaglinide) act as inhibitors that bind to SUR1, leading to the closure of the K-ATP channel [3, 5]. This results in membrane depolarization, opening of voltage-gated calcium channels, and subsequent insulin exocytosis from pancreatic beta cells [2, 8]. Conversely, potassium channel openers like diazoxide bind to SUR1 to maintain the channel in an open state, causing hyperpolarization and inhibiting insulin release [3, 11]. In the context of CNS injury, SUR1 inhibitors prevent the opening of SUR1-TRPM4 channels, thereby reducing oncotic cell swelling and cerebral edema [9, 10].