ATP sensitive potassium channels (K ) are so named because they open as cellular ATP levels fall. This leads to membrane hyperpolarization and thus links cellular metabolism to membrane excitability. They also respond to MgADP and are regulated by a number of cell signaling pathways. They have a rich and diverse pharmacology with a number of agents acting as specific inhibitors and activators. K channels are formed of pore-forming subunits, Kir6.1 and Kir6.2, and a large auxiliary subunit, the sulfonylurea receptor (SUR1, SUR2A, and SUR2B). The Kir6.0 subunits are a member of the inwardly rectifying family of potassium channels and the sulfonylurea receptor is part of the ATP-binding cassette family of proteins. Four SURs and four Kir6.x form an octameric channel complex and the association of a particular SUR with a specific Kir6.x subunit constitutes the K current in a particular tissue. A combination of mutagenesis work combined with structural studies has identified how these channels work as molecular machines. They have a variety of physiological roles including controlling the release of insulin from pancreatic β cells and regulating blood vessel tone and blood pressure. Furthermore, mutations in the genes underlie human diseases such as congenital diabetes and hyperinsulinism. Additionally, opening of these channels is protective in a number of pathological conditions such as myocardial ischemia and stroke. © 2018 American Physiological Society. Compr Physiol 8:1463-1511, 2018.

ATP-sensitive potassium channels (KATP) are widely distributed and present in a number of tissues including muscle, pancreatic beta cells and the brain. Their activity is regulated by adenine nucleotides, characteristically being activated by falling ATP and rising ADP levels. Thus, they link cellular metabolism with membrane excitability. Recent studies using genetically modified mice and genomic studies in patients have implicated KATP channels in a number of physiological and pathological processes. In this review, we focus on their role in cellular function and protection particularly in the cardiovascular system. AbbreviationsABC, ATP binding cassette; AP, action potential; KATP, ATP-sensitive potassium channel; KCO, ATP-sensitive potassium channel opening drug; PIP2, phosphatidyl 4,5-bisphosphate; SUR, sulphonylurea receptor; VSM, vascular smooth muscle IntroductionTwo independent laboratories can lay claim to having first described the ATP-sensitive potassium channels (KATP; channel nomenclature follows Alexander et al., 2013). Noma (1983) observed the appearance of an outward K + current in heart muscle cells when treated with metabolic poisons or hypoxia. This was reversed by ATP injected into the cell. Similar observations were made by another group (Trube and Hescheler, 1984). Such channels were subsequently described in pancreatic beta cells (Ashcroft et al., 1984), skeletal muscle (Spruce et al., 1985), smooth muscle (Standen et al., 1989) and neurones (Ashford et al., 1988). During this period, the basic electrophysiological and pharmacological properties of the channel were elucidated (Ashcroft, 1988;Noma and Takano, 1991). In inside-out patches in ∼140 mM symmetrical K + concentrations, the single-channel conductance is ohmic with a conductance of 70-80 pS. The lower values sometimes noted in the literature generally have lower and asymmetric K + concentrations. The channel is highly selective for potassium (PNa/PK∼0.01). Activity is inhibited by the application of ATP with a Ki of 10-500 μM with a Hill coefficient of more than 1 (generally around 2) depending on the tissue and recording configuration. The ATP inhibition is not dependent on ATP hydrolysis: it is not reliant on Mg 2+ and ATP can be substituted by non-hydrolysable derivatives. In the absence of magnesium other adenine nucleotides can inhibit channel activity but they are less potent. However, in the presence of Mg 2+ and ATP, ADP is stimulatory. Even at the beginning of the 1990s the channels were known to have a rich pharmacology (see Edwards and Weston, 1993). Sulphonylureas were discovered accidentally when it was noted that the anti-microbial sulphonamides caused hypoglycaemia in animals. It became apparent that stimulation of insulin release from pancreatic beta cells occurred because of inhibition of KATP channels. There is a family of these drugs: the most widely known are the firstgeneration agents (e.g. tolbutamide, chlorpropamide) and the more potent second-generation agents (e.g. glibenclamide, gliclazide, glipizide). Th...

A TP-sensitive potassium channels (K ATP ) are widely expressed in a range of tissues, including brain, heart, pancreas, and smooth muscle (SM), where they are involved in the regulation of biological processes such as insulin release, vascular tone, and adaptation to stresses such as ischemia and hypoxia. They are activated by either declining ATP or increasing ADP concentrations or both, thus coupling intracellular metabolism to membrane excitability. 1 K ATP channels are composed of 4 pore-forming Kir6.x subunits (Kir6.1 or Kir6.2) and 4 large regulatory sulphonylurea receptor subunits (SUR1, SUR2A or SUR2B) to form a functional hetero-octomeric complex.1 The vascular SM K ATP channel is thought to be composed of the Kir6.1 and SUR2B subunits.2,3 These SM K ATP channels have been implicated in the regulation of vascular tone through their proposed involvement in the actions of vasoconstrictors and vasodilators. [4][5][6][7] The integrative physiological role of these channels has been investigated in mice with global genetic deletion of either Kir6.1 or SUR2. 8,9 The mice were hypertensive and prone to sudden death, which was attributed to coronary artery vasospasm because of the absence of K ATP currents in the SM of the coronary arteries. However, when SUR2B was specifically expressed in SM in SUR2 global knockout mice resulting in reconstitution of the K ATP current, the lethal phenotype persisted.10 Furthermore, transgenic expression of SUR2A in cardiomyocytes in SUR2 null mice led to a dramatic reduction in the degree and frequency of episodes of ST elevation on the ECG measured using telemetry.11 The implication was that reconstitution of K ATP in cardiac myocytes led to a reduction of coronary artery SM spasm and it was proposed that K ATP channels outside the SM cell (SMC) are critical in driving the vascular phenotype in the global knockout mice and that the vascular SM K ATP channel contributes modestly to vascular control. 10 A global genetic deletion of Kir6.1 or SUR2 is not selective for the SM channel and potentially channels in the endothelium, nervous system, and heart might all be affected. Here, using a new mouse model, we show that Kir6.1 is indeed the pore-forming subunit of the K ATP channel in vascular SM and that it has a central role in the regulation of blood pressure (BP).Abstract-ATP-sensitive potassium channels (K ATP ) regulate a range of biological activities by coupling membrane excitability to the cellular metabolic state. In particular, it has been proposed that K ATP channels and specifically, the channel subunits Kir6.1 and SUR2B, play an important role in the regulation of vascular tone. However, recent experiments have suggested that K ATP channels outside the vascular smooth muscle compartment are the key determinant of the observed behavior. Thus, we address the importance of the vascular smooth muscle K ATP channel, using a novel murine model in which it is possible to conditionally delete the Kir6.1 subunit.

ATP-sensitive potassium (K) channels are widely expressed in the cardiovascular system, where they regulate a range of biological activities by linking cellular metabolism with membrane excitability. K channels in vascular smooth muscle have a well-defined role in regulating vascular tone. K channels are also thought to be expressed in vascular endothelial cells, but their presence and function in this context are less clear. As a result, we aimed to investigate the molecular composition and physiological role of endothelial K channels. We first generated mice with an endothelial specific deletion of the channel subunit Kir6.1 (eKO) using cre-loxP technology. Data from qRT-PCR, patch clamp, coronary perfusion Langendorff heart experiments, and endothelial cell Ca imaging comparing eKO and wild-type mice show that Kir6.1-containing K channels are indeed present in vascular endothelium. An increase in intracellular [Ca], which is central to changes in endothelial function such as mediator release, at least partly contributes to the endothelium-dependent vasorelaxation induced by the K channel opener pinacidil. The absence of Kir6.1 did not elevate basal coronary perfusion pressure in eKO mice. However, vasorelaxation was impaired during hypoxia in the coronary circulation, and this resulted in greater cardiac injury during ischemia-reperfusion. The response to adenosine receptor stimulation was impaired in eKO mice in single cells in patch clamp recordings and in the intact coronary circulation. Our data support the existence of an endothelial K channel that contains Kir6.1, is involved in vascular reactivity in the coronary circulation, and has a protective role in ischemia reperfusion.