SUR1directed

SUR1directed refers to therapeutic approaches and research efforts that target the sulfonylurea receptor 1 (SUR1), the regulatory subunit of ATP-sensitive potassium (KATP) channels encoded by the ABCC8 gene. This term encompasses pharmacologic, genetic, and molecular strategies designed to modulate SUR1-containing channels in various tissues.

In the pancreas, SUR1 forms a KATP channel with Kir6.x in beta cells, regulating insulin secretion. In the brain and other tissues, SUR1 can associate with TRPM4 to create a SUR1-TRPM4 complex linked to cellular edema after injury. SUR1-directed strategies thus aim to inhibit SUR1-containing channels to modulate hormone release in metabolic disorders and to mitigate pathological processes such as edema in neurological injuries.

Therapeutic approaches include repurposing or developing SUR1-binding agents. Sulfonylureas such as glyburide (glibenclamide), glipizide, and gliclazide bind SUR1 and inhibit channel activity, a mechanism exploited in certain monogenic forms of diabetes caused by ABCC8 or KCNJ11 mutations where sulfonylureas can enable oral glycemic control. In neurology, SUR1-directed therapy focuses on reducing cerebral edema by blocking the SUR1-TRPM4 complex; preclinical studies and early clinical investigations have explored glibenclamide for outcomes after stroke and traumatic brain injury, with mixed results to date.

Status and challenges include balancing efficacy with hypoglycemia risk, achieving tissue-selective targeting, and ensuring adequate central nervous system penetration. Ongoing research seeks more selective SUR1 modulators and strategies to harness SUR1-directed therapies safely across different diseases.

See also: SUR1, ABCC8, KATP channels, SUR1-TRPM4.