THE SULFONYLUREA RECEPTOR: AN ABCC TRANSPORTER THAT ACTS AS AN ION CHANNEL REGULATOR

The sulfonylurea receptor (SUR) serves as the regulatory subunit of the ATP-sensitive potassium (KATP) channel, endowing it with the ability to respond to changes in cell metabolism. The KATP channel is a hetero-octameric complex of four Kir6.x and four SUR subunits. Kir6.x belongs to the family of inwardly rectifying K channels and assembles into tetramers to form the channel. Binding of ATP to the intracellular domains of Kir6.x produces channel inhibition. Associated with each Kir6.x subunit is a regulatory subunit, the sulfonylurea receptor (SUR). SUR has two large intracellular domains, containing consensus sequences for nucleotide binding and hydrolysis, which are known as the nucleotide binding domains (NBDs). Interaction of Mg-nucleotides with these NBDs mediates activation of the KATP channel. The SUR subunit also binds therapeutic drugs, such as the sulfonyl ureas, which inhibit KATP channel activity, and the KATP channel openers that stimulate channel activity. Kir6.2 serves as the pore-forming subunit, but it associates with different SUR subunits: for example, SUR1 in pancreas and brain, SUR2A in heart, and skeletal muscle and SUR2B in a variety of tissues including brain and smooth muscle. In some smooth muscles, the KATP channel comprises Kir6.1 in association with SUR2B. This chapter focuses on the physiological role of the KATP channel and how this is impaired in disease. It then discusses the molecular composition of the KATP channel, and details its regulation by nucleotides, metabolism and other signaling molecules. Finally, what is known of the pharmacological properties of the channel is summarized.