New insights into the tissue specificity of sulphonylureas

Abstract

Sulphonylureas stimulate insulin secretion in type-2 diabetic patients by closing ATP-sensitive (KATP) potassium channels in the plasma membrane of pancreatic b-cells. This effect is mediated by binding of the drug to the sulphonylurea receptor (SUR 1) subunit of the channel. KATP channels are formed of two different types of subunit: a pore-forming subunit (usually Kir 6.2) and a sulphonylurea receptor subunit (SUR), which associate in a 4:4 heteromeric complex. Several different isoforms of SUR are known and KATP channels in different tissues possess different types of SUR subunit (SUR 1 in b-cells, SUR 2A in heart, and SUR 2B in smooth muscle). The sulphonylurea-sensitivity of KATP channels varies with the type of SUR subunit: thus, gliclazide and tolbutamide potently block the b-cell, but not the cardiac or smooth muscle types of KATP channel. In contrast, glibenclamide and glimepiride block all three types of KATP channel with similar potency.