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	Figure 1. Recordings of single KATP channels. Cell‐attached single channel recordings of Kir6.2/SUR2B channels expressed in HEK293 cells. Coexpression of Kir6.2/SUR2B forms a channel with a single channel conductance of ∼70 pS.
	Figure 2. The structure of drugs acting on KATP channels.
	Figure 3. A cartoon of the molecular composition of a KATP channel. KATP channels are formed from four pore‐forming Kir6.x subunits and four regulatory sulfonylurea receptor subunits. Kir6x is a member of the inward‐rectifying K+ channel family (Kir) with two transmembrane domains (M1 and M2), a pore‐forming region (H5) with the K+ selectivity sequence and intracellular N and C termini. SUR belongs to the ATP binding cassette (ABC) family of proteins. SUR consists of three transmembrane domains (TMDs) composed of five, six, and six transmembrane segments, respectively. The intracellular loop between TMD0 and TMD1, L0 provides the physical interaction with Kir6x. Two nucleotide‐binding domains (NBD1 and NDB2) comprised of Walker A and B nucleotide binding motifs provide the binding sites for magnesium complexed adenine nucleotides.
	Figure 4. The high‐resolution structure of the pancreatic KATP channel. (A) The linear sequence of Kir6.2 and SUR1 proteins. The various critical domains are colored and the same scheme is used in the other panels. The numbers indicate amino acid residues defining the regions. (B) A side view of the cryo‐EM density map of the KATP channel (3.6 Å resolution). The position of the membrane is indicated by the gray bars. (C) An extracellular view of the complex. (D) A model of the KATP channel complex with various ligands as indicated (ATP is green and glibenclamide is red). (E) The model viewed from the extracellular side of membrane. This figure is reproduced, with permission, from the recent study (342).
	Figure 5. The ATP binding pocket in Kir6.2 determined in the quatrefoil form. (A) An EM density of the Kir6.2 tetramer with ATP molecules shown in yellow. (B) A ribbon representation of Kir6.2 with two pore domains shown with important structural elements indicated. The ATP molecule is again shown in yellow. (C) The ATP‐binding site with residues contacting the yellow ATP as indicated. The N‐terminus from the neighboring subunit interacts with the purine base of ATP. Dashed lines indicate hydrogen bonds. (D) The EM density of the ATP molecule is outlined with a blue mesh and illustrates a horseshoe‐shaped conformation. This figure is reproduced, with permission, from the recent study (305).
	Figure 6. Proposed sites of action of KATP openers and inhibitors. The aforementioned schematics demonstrate the pharmacotopology with respect to the different sulfonylurea receptor subtypes. The color of the various segments of each SUR demonstrates broadly the homology between the subtypes. SUR2A and SUR2B (red) share almost 100% homology and that which is different from SUR1 (blue). However, the terminal 42 amino acids of the C terminus of SUR2A and SUR2B differ, and in fact, this segment in SUR1 shares almost 100% homology with that in SUR2B as depicted by the color coding in blue. Openers and their sites of action are depicted in green and inhibitors black. Capital letters denotes binding with high affinity and lower case with lower affinity. The action of diazoxide on SUR2A is shown in darker green given the fact that this interaction requires the presence of a high concentration of MgADP, and this probably results allosterically due to the differing terminal 42 amino acids at the C terminus of SUR2A (368).
	Figure 7. The regulation of vascular smooth muscle KATP channels. Activation or inhibition of KATP channels in the vascular smooth muscle cell determines its membrane potential. Vasoactive factors that activate KATP channels either directly or indirectly cause membrane hyperpolarization, closure of voltage‐dependent calcium channels, reduced intracellular Ca2+, and dilation. Conversely, factors that inhibit KATP channels cause depolarization of the cell membrane leading to opening of voltage‐dependent calcium channels, increased intracellular Ca2+, and contraction. Left, dilation of VSM as a result of KATP channel activation initiated by vasodilators such as adrenaline, adenosine, calcitonin gene‐related peptide (CGRP), and vasoactive intestinal peptide (VIP) via the G‐protein (Gs)/Adenylate Cyclase (AC)/Protein Kinase A (PKA) signaling pathway. Hypoxia, ischemia, and metabolic stress indirectly activate KATP channels by inhibiting oxidative phosphorylation and therefore decreasing the ATP/ADP ratio. Right, endogenous mediators such as noradrenaline, angiotensin II, endothelin‐1, and histamine inhibit KATP channels via the G‐protein (Gi, q)/PKC signaling pathway leading to VSM contraction.
	Figure 8. A cartoon of stimulus‐secretion coupling in pancreatic β cells. KATP channels couple cellular metabolism to electrical activity. When blood glucose is low, ATP production is reduced allowing KATP channels to open thus hyperpolarizing the membrane and preventing an increase intracellular Ca2+ and subsequent insulin release. When there is a high blood glucose concentration, ATP production increases leading to channel inhibition, an increase in intracellular Ca2+ and insulin release.
	Figure 9. Disease mechanisms in hereditary channelopathies. The route to delivery of fully and normally functioning ion channels at the cell membrane can be halted or disturbed at various checkpoints. Mutations can lead to: (1) defective transcription or translation such that channel proteins are merely not synthesized at all. (2) Aberrant folding of channel proteins into their tertiary and quaternary structures that is recognized by chaperone proteins in the endoplasmic reticulum and leads to their degradation and failure to exit the endoplasmic reticulum. (3) Further quality control in the Golgi complex where channels can still be recognized as faulty and retro‐translocated back to the endoplasmic reticulum or assigned for degradation. (4) Defective cycling to and from the membrane through exo‐ and endocytosis. (5) Channels that pass through all the checkpoints and are delivered to the membrane but which display abnormal gating and/or kinetics, or abnormal responses to modulatory pathways.
	Figure 10. The pathogenesis of hereditary hyperinsulinism and diabetes due to mutations in KATP channels. Loss of function mutations leads to excessive insulin release and hypoglycemia. In contrast, gain of function mutation affect ATP sensitivity and impair insulin release from pancreatic beta cells resulting in diabetes.
	Figure 11. Protective role of KATP channels in cardiomyocytes. Activation of KATP channels by protein kinase C or metabolic insults such as ischemia and/or hypoxia stabilizes the membrane potential, leads to shortening of the action potential duration, and reduces the influx of calcium through voltage‐dependent calcium channels. This attenuates calcium‐induced calcium release from the sarcoplasmic reticulum, which reduces contractility, prevents calcium overload, and decreases ATP demand.

Teaching Material

A. Tinker, Q. Aziz, Y. Li, M. Specterman. ATP-Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles. Compr Physiol 8: 2018, 1463-1511.

Didactic Synopsis

Major Teaching Points:

• ATP-sensitive potassium channels (K_ATP) are widely distributed and characteristically are activated by falling cellular ATP levels.
• K_ATP channels link membrane excitability to cellular metabolism.
• K_ATP channels have a rich and diverse pharmacology with specific inhibitors such as glibenclamide and openers such as diazoxide.
• The channel is an octamer formed of four inwardly rectifying potassium channels of the Kir6.0 family and four sulfonylurea receptor subunits, a member of the ATP binding cassette family of proteins.
• Extensive mutagenesis experiments and recent structural studies have defined many aspects of how the channel works as a molecular machine.
• K_ATP channels are key to the release of insulin from pancreatic β cells.
• K_ATP channels in the heart are involved in adaptation to exercise and cellular protection and in vascular smooth muscle controlling vascular tone and blood pressure.
• K_ATP channels are present in the brain and may be involved in neuroprotection and nutrient sensing.
• Mutations in K_ATP channel subunits can result in human disease and includes disorders of insulin handling, cardiac arrhythmia, cardiomyopathy, and neurological abnormalities.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Teaching points: Ion channels have an open and closed conformation and when open pass a current with a characteristic conductance. The figure illustrates such high-resolution single channel recordings of KATP channels using the patch-clamp recording technique.

Figure 2 Teaching points: KATP channels have a rich pharmacology with a variety of pharmacophores able to selectively inhibit or activate the currents.

Figure 3 Teaching points: We understand the molecular composition of KATP channels. They are composed of four inwardly rectifying potassium channel subunits (Kir6.1 and Kir6.2) and four sulfonylurea receptors (SUR1, SUR2A, and SUR2B) which are a member of the large family of ATP binding cassette proteins. ATP inhibits the channel by binding to the channel pore forming subunit while MgADP, sulfonylureas, and potassium channel openers act on the sulfonylurea receptors. The channels in different tissues have different properties and this is accounted for by selective expression of different Kir6.0 subunits and different SURs.

Figure 4 Teaching points: One of the major advances has been the determination of crystal structures of KATP channels using cryo-EM. These have revealed their characteristic structural features and given insight into how glibenclamide might bind and inhibit the channel.

Figure 5 Teaching points: The defining feature of KATP channels is their sensitivity to nucleotide levels and ATP in particular thus enabling them to link cellular metabolism and membrane potential. The crystal structures show in exquisite molecular detail how ATP binds to the Kir6.2 subunit.

Figure 6 Teaching points: The drugs that work on KATP channels show some tissue selectivity accounted for by differential Kir6.0 and SUR expression.

Figure 7 Teaching points: KATP channels are critically involved in many physiological processes. In vascular smooth muscle cells, they significantly influence vascular smooth tone and both vasodilators and vasoconstrictors can modulate activity through direct protein phosphorylation of the channel subunits.

Figure 8 Teaching points: KATP channels are critically involved in many physiological processes. The best described are their role in stimulus secretion coupling in the pancreas. Increases in blood glucose are tightly coupled to ATP production in pancreatic beta resulting in channel inhibition, membrane depolarization, and entry of calcium, which promotes the release of insulin vesicles.

Figure 9 Teaching points: An emerging theme has been the involvement of ion channels in human disease known as “channelopathies.” For example, defects in KATP channels lead to disorders of insulin handling through gain and loss of function mutations. This can occur through many different mechanisms and not simply changes in the activity of the channel at the plasma membrane. Differences in channel trafficking through the secretory pathway and in endocytosis may also be involved.

Figure 10 Teaching points: The critical role of role of KATP channels in insulin release is reinforced by human hereditary diseases of both excessive and reduced insulin release, which result from mutations in the genes underlying subunits of KATP channels.

Figure 11 Teaching points: KATP channels in the heart and elsewhere are protective to the cell. One of the main ideas in the heart is that this limits calcium entry and release reducing muscle contraction, calcium overload, and ATP demand.