Sulfonylurea receptor–associated channels

The sulfonylurea receptors (SURs) 1 (SUR1) and 2 (SUR2) are members of the adenosine triphosphate (ATP) binding cassette transporters superfamily. Unlike other members of this superfamily, these receptors are not involved in transport but associate with pore-forming subunits to form cation channels. Both SUR1 and SUR2 associate with inward rectifying potassium (K⁺) (Kir) channels (Kir6) subunits to form functional ATP-sensitive K⁺ channels (K_ATP).¹ These channels are molecular sensors that provide a link between cellular energy state and electrical excitability; they are tonically inhibited by ATP, and their activation in the setting of energy failure results in cell hyperpolarization and vasodilation, leading to cell-protective effects. SUR1 also associates with the pore-forming subunit of the calcium (Ca²⁺) activated transient receptor potential melastatin 4 (TRPM4) channel.² In contrast to K_ATP channels, the SUR1-regulated TRMP4 channels are nonselective monovalent cation channels that trigger depolarization and cerebral vasoconstriction. Upregulation of SUR1-TRPM4 channels in conditions such as cerebral ischemia may result in necrotic cell death, affecting the neurovascular unit and promoting cerebral edema. Whereas in normal conditions K_ATP channels exert neuroprotective effects, in pathologic conditions their excessive activation may also be deleterious. The presence of regulatory SUR subunits renders K_ATP and TRPM4 channels sensitive to inhibition by sulfonylureas such as glibenclamide (glyburide). Preclinical evidence from experimental models and early clinical trials indicate that this drug may be of therapeutic benefit in conditions such as that described in this representative case.^3,4