SUR-2 Activators

SUR-2, also known as sulfonylurea receptor 2, is an integral component of ATP-sensitive potassium (KATP) channels, which are crucial regulators of cellular excitability and insulin secretion in pancreatic beta cells and other excitable tissues. Functionally, SUR-2 acts as a regulatory subunit of KATP channels, modulating their sensitivity to intracellular ATP and ADP levels. KATP channels consist of inwardly rectifying potassium channel subunits (Kir6.x) and regulatory SUR subunits, forming hetero-octameric complexes that reside in the plasma membrane. Under physiological conditions, high intracellular ATP concentrations inhibit KATP channel activity by binding to SUR-2, promoting channel closure and membrane depolarization. Conversely, decreased ATP levels or increased ADP levels relieve this inhibition, leading to KATP channel opening, potassium efflux, and membrane hyperpolarization, which inhibit cellular excitability and promote insulin release in pancreatic beta cells. Beyond its role in pancreatic beta cells, SUR-2-mediated KATP channel regulation also influences cardiovascular function, smooth muscle tone, and neuronal excitability, highlighting its importance in diverse physiological processes.

Activation of SUR-2 is governed by multiple regulatory mechanisms that modulate its interaction with nucleotides, drugs, and regulatory proteins. Binding of intracellular ATP to SUR-2 induces conformational changes that stabilize the closed state of KATP channels, inhibiting potassium efflux and maintaining cellular quiescence. Conversely, nucleotide binding to the nucleotide-binding domains (NBDs) of SUR-2 can trigger channel opening in response to metabolic stress or pharmacological agents such as sulfonylurea drugs. Moreover, post-translational modifications, including phosphorylation and palmitoylation, regulate SUR-2 activity and subcellular localization, influencing KATP channel function and cellular excitability. The dynamic interplay between these regulatory mechanisms ensures precise control over KATP channel activity in response to metabolic and pharmacological cues, contributing to the maintenance of cellular homeostasis and physiological function.