The surprising role of vascular K(ATP) channels in vasospastic angina.

Abstract

The golden age of single-channel electrophysiology was punctuated by the discovery of a curious class of potassium-selective channels in the surface membranes of heart cells (1, 2). These channels, silent under normal metabolic conditions, become robustly active when submembrane ATP is depleted. The opening of such KATP channels was soon recognized to underlie the loss of cellular excitability during metabolic stress (3, 4) and (later, in an in vivo correlate) to mediate the so-called ST segment elevation, an electrocardiographic change diagnostic of transmural injury during prolonged coronary ischemia (5). While these channels were discovered in heart cells, they are broadly-distributed throughout the body; their most obvious physiological role is in the pancreas, where they transduce changes in glucose concentration into alterations of β cell excitation and insulin secretion (6). Ironically, the role of KATP channels in the heart, where they were first discovered, remains mysterious. In the present issue and in recent work published elsewhere, new surprises emerge regarding the identities and the roles of KATP channels in the vasculature. The general molecular structure of KATP channels was clarified by the pioneering work of the Bryan, Aguilar-Bryan (7) and Seino laboratories (8). KATP channels turn out to be complex hetero-octamers of four subunits encoded by sulfonylurea receptor (Sur) genes, surrounding a central pore made up of four Kir6-encoded K channel subunits (9). Different tissues express different permutations of the three possible Surs (Sur1, and the Sur2 splice variants, Sur2A and Sur2B) and two pore-forming subunits (Kir6.1 and Kir6.2). The conventional surface KATP channels in the heart are formed by Sur2 and Kir6.2, whereas those in pancreatic β cells consist of Sur1 and Kir6.2. KATP channels have a rich pharmacology (10), including a number of venerable vasodilators (e.g., the KATP channel agonists diazoxide and minoxidil) and anti-diabetic agents (notably the KATP channel blocker glybenclamide), which were in clinical use long before their targets were recognized.