Molecular biology of K_ATP channels and implications for health and disease

Abstract

Summary The ATP-sensitive potassium (KATP) channel is expressed in most excitable tissues and plays a critical role in numerous physiological processes by coupling intracellular energetics to electrical activity. The channel is comprised of four Kir6.x subunits associated with four regulatory sulfonylurea receptors (SUR). Intracellular ATP acts on Kir6.x to inhibit channel activity, while MgADP stimulates channel activity through SUR. Changes in the cytosolic [ATP] to [ADP] ratio thus determine channel activity. Multiple mutations in Kir6.x and SUR genes have implicated KATP channels in various diseases ranging from diabetes and hyperinsulinism to cardiac arrhythmias and cardiovascular disease. Continuing studies of channel physiology and pathology will bring new insights to the molecular basis of KATP channel function, leading to a better understanding of the role that KATP channels play in both health and disease.

Salvinorin A Produces Cerebrovasodilation through Activation of Nitric Oxide Synthase, κ Receptor, and Adenosine Triphosphate–sensitive Potassium Channel

“…Membrane potential changes would then regulate muscle relaxation through alterations in Ca 2+ influx through voltage-dependent Ca 2+ channels. 17,18 To our knowledge, this is the first study to demonstrate that salvinorin A actives the K ATP channel directly or indirectly. Different from many other agents that can activate the K ATP channel, salvinorin A can easily penetrate the blood-brain barrier.…”

Mitochondria and arrhythmias

“…The Kir α-subunits, like Kv channels, assemble as tetramers to form functional Kir channels [39, 152, 153], although Kir α-subunits have only two, instead of six, transmembrane domains. It has been shown that cardiac I K1 channels reflect the heteromeric assembly of the Kir α-subunits, Kir 2.1 and Kir 2.2 [154–158] and that the predominant form of K ATP channels in cardiac sarcolemma reflects the assembly of Kir6.2 and SUR2A [159]. While Kv currents contribute importantly to the repolarization of action potentials in mammalian ventricular myocardium, the Kir currents also contribute to shaping the resting and active membrane properties of cardiomyocytes.…”

Vascular KATP channels mitigate severe muscle O2 delivery-utilization mismatch during contractions in chronic heart failure rats

“…Thus, K ATP channel activation via NO is likely mediated through a combination of these two mechanisms. The notion that K ATP channels can amplify vasodilatory signaling (Cole et al, 2000; Silva et al, 2008) via modulation of membrane potential deserves further investigation and may be valuable clinically (Akrouh et al, 2009). …”