ATP-sensitive K⁺ channels in pancreatic, cardiac, and vascular smooth muscle cells

Abstract

ATP-sensitive K+(KATP) channels are therapeutic targets for several diseases, including angina, hypertension, and diabetes. This is because stimulation of KATP channels is thought to produce vasorelaxation and myocardial protection against ischemia, whereas inhibition facilitates insulin secretion. It is well known that native KATP channels are inhibited by ATP and sulfonylurea (SU) compounds and stimulated by nucleotide diphosphates and K+channel-opening drugs (KCOs). Although these characteristics can be shared with KATP channels in different tissues, differences in properties among pancreatic, cardiac, and vascular smooth muscle (VSM) cells do exist in terms of the actions produced by such regulators. Recent molecular biology and electrophysiological studies have provided useful information toward the better understanding of KATPchannels. For example, native KATPchannels appear to be a complex of a regulatory protein containing the SU-binding site [sulfonylurea receptor (SUR)] and an inward-rectifying K+ channel (Kir) serving as a pore-forming subunit. Three isoforms of SUR (SUR1, SUR2A, and SUR2B) have been cloned and found to have two nucleotide-binding folds (NBFs). It seems that these NBFs play an essential role in conferring the MgADP and KCO sensitivity to the channel, whereas the Kir channel subunit itself possesses the ATP-sensing mechanism as an intrinsic property. The molecular structure of KATPchannels is thought to be a heteromultimeric (tetrameric) assembly of these complexes: Kir6.2 with SUR1 (SUR1/Kir6.2, pancreatic type), Kir6.2 with SUR2A (SUR2A/Kir6.2, cardiac type), and Kir6.1 with SUR2B (SUR2B/Kir6.1, VSM type) [i.e., (SUR/Kir6. x)4]. It remains to be determined what are the molecular connections between the SUR and Kir subunits that enable this unique complex to work as a functional KATP channel.

ATP-sensitive potassium currents reduce the PGE2-mediated enhancement of excitability in adult rat sensory neurons

“…Because these channels are regulated by the levels of ATP, they provide an important link between cellular metabolism and excitability (Kakei et al 1985;Kakei et al 1986;Ashcroft 1988;Ashcroft and Kakei 1989). In this regard, K ATP channels control the release of insulin from pancreatic β cells (Ashcroft et al 1984;Ashcroft and Gribble 1998;Miki et al 1999;Schwanstecher et al 1998;Seino 1999) and blood flow in muscle, heart, and kidney tissue (Ashcroft 1988;Nelson and Quayle 1995;Terzic et al 1995;Yokoshiki et al 1998). In neurons, activation of K ATP results in membrane hyperpolarization that reduces excitability (Yamada et al 2001;Allen and Brown 2004) and activation of presynaptic K ATP channels can directly modulate neurotransmitter release from nerve terminals (Deist et al 1992;Ohno-Shosaku et al 1992;Watts et al 1995;Ye et al 1997).…”

Distribution of Kir6.0 and SUR2 ATP-sensitive potassium channel subunits in isolated ventricular myocytes

“…1 Although these channels would normally be closed in cardiac myocytes, during myocardial ischemia, where the cellular ATP:ADP ratio falls substantially, activation of K ATP channels could contribute to cardioprotective mechanisms. 2,3 Functional K ATP channel currents have been demonstrated in both cardiac sarcolemmal 4 (sarcK ATP ) and mitochondrial (mitoK ATP ) membranes 5 .…”

“…7 The pharmacological properties of channels expressed in heterologous systems suggest strongly that the sarcK ATP channel is composed of Kir6.2 and SUR2A subunits. 1 Current flow via Kir6.2 subunits in sarcK ATP channels is integral to mechanisms of action potential shortening. This was shown by the rescue of pinacidilinduced outward current and action potential shortening in ventricular cells from Kir6.2 -/-knockout mice by gene transfer of the Kir6.2 subunit.…”

“…To date, the SUR2B subunit has been associated primarily with K ATP channels in the sarcolemma of smooth muscle. 1 Specific localization of SUR2B to the ttubules of cardiomyocytes suggests a possible novel function in this location. The inward rectifiers Kir2.1 and Kir2.2 have both been implicated in contributing to a slow inward tail current (I tail ) in t-tubules of ventricular myocytes.…”

Molecular basis and characteristics of KATP channel in human corporal smooth muscle cells

“…Adenosine 5 0 -triphosphate-sensitive potassium (K ATP ) channels are widely distributed in a variety of tissue and cell types, where they couple intracellular metabolic changes to the electrical activity of the plasma membrane, thus playing an important role in both physiology and pathology. Electrophysiological studies have shown that the kinetics and pharmacological properties of K ATP channels vary among different tissues, 1 suggesting structurally and functionally distinct types.…”