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Molecular Biology of KATP Channels and Implications for Health and Disease


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.

Keywords: KATP channels, diabetes, hyperinsulinism, cardiovascular, SUR, Kir6.2


ATP-sensitive potassium (KATP) channels sit at the cross-roads of cell metabolism and membrane excitability. These members of the family of inwardly rectifying K+ channels are activated by Mg2+-bound nucleotides and inhibited by intracellular ATP (1). Thus, KATP channels are open during states of low metabolic activity, resulting in hyperpolarization of the membrane, which has cytoprotective effects in vascular and neural tissues (2, 3). In high metabolism, KATP channel activity decreases and the resulting membrane depolarization triggers cellular responses such as insulin secretion (4). First described in ventricular myocytes (5, 6), KATP channels have been found in tissues throughout the body, including pancreatic β-cells (7), skeletal muscle (8), visceral and vascular smooth muscle (9), and brain (10, 11). Although roles in glucose homeostasis and ischemic protection are well established (1214), novel functions of KATP channels continue to emerge: recognized as protective against neural apoptosis following a stroke (3), brain KATP channels have recently been implicated in memory (15) and in the regulation of male reproductive behavior (16). Mutations leading to absent, decreased, or hyperactive KATP channels have been linked to a variety of diseases, from mild and transient to severe and permanent neonatal diabetes (1719), and efforts continue to be made to understand the implications of KATP channels in health and disease. Classic KATP channel openers, such as diazoxide and pinacidil, have been used to treat hypertension, angina, and hyperinsulinism of infancy, while antagonists such as sulfonylureas are established antidiabetic agents (20). The drug industry continues to exploit the tissue specific pharmacology of KATP channels in the design of novel therapeutic agents aimed at endocrine, vascular, neurological, urological, and even dermatological ailments (21). Here, we will summarize current understanding of the molecular biology, pharmacology, and physiology of KATP channels and the disease states that result from aberrant expression or function of these proteins, with a special focus on the pancreas and the cardiovascular system.


Channel Architecture and Assembly

ATP-sensitive potassium (KATP) channels are large heteromeric protein complexes that confer their native tissue with a hyperpolarizing potassium conductance which is modulated by the energetic state of the cell. The channel is established by four pore-forming subunits that belong to the family of inwardly rectifying potassium (Kir) channels. The two subtypes found in KATP channels, Kir6.1 and Kir6.2 (22, 23), are encoded by KCNJ8 and KCNJ11, respectively, and both are inhibited by cytosolic ATP (24). Kir6.2 is the major pore-forming subunit in pancreatic and cardiac cells while Kir6.1 is predominant in smooth muscle tissue. Although heteromultimerization of Kir6.1 and Kir6.2 has been disputed (25), there is evidence to suggest that the two subtypes may in fact be found together in some native channels (26).

The Kir6.x tetramer is associated with four sulfonylurea receptors (SURx) (27, 28) which belong to the broad and diverse family of ATP-binding cassette (ABC) proteins (Fig. 1). In particular, two genes code for SURx; ABCC8 encodes SUR1 while ABCC9 gives rise to two splice variants, SUR2A and SUR2B (29, 30). Through SURx, KATP channels are inhibited by sulfonylureas and activated by diazoxide (SUR1) and pinacidil (SUR2) (1). Physiologically, KATP channels are stimulated by intracellular magnesium nucleotides, which interact with the nucleotide binding folds of SURx, and, depending on the energetic state of the cell, can overcome ATP inhibition of Kir6.x to open the channel pore. Interestingly, SUR1 has been shown to exhibit higher in vitro ATP hydrolysis than SUR2A (31), and is more sensitive to MgADP activation.

Figure 1
Membrane topology of Kir6.x and SURx and KATP channel assembly. A: Kir6 subunits consist of two transmembrane helices (M1 and M2) connected by a ‘P-loop’ which defines the selectivity filter of the channel. SUR is composed of two six-helix ...

The genes that encode human Kir6.2 and SUR1 lie sequentially on chromosome 11, while those encoding Kir6.1 and SUR2 lie sequentially on chromosome 12 (30). The similarity between the two gene pairs and the symmetry of Kir6.x and SURx gene location implicate an evolutionary duplication event. However, the combination of subunits extends beyond the pairing of Kir6.2 with SUR1 and Kir6.1 with SUR2. In fact, there is a growing body of evidence that suggests that all combinations of Kir6.x and SURx are likely to be expressed in functional channels in one tissue or another, as elaborated later.

KATP Channel Open Probability (Po) and ATP Sensitivity are Correlated

Phosphatidylinositol-4,5-bisphosphate (PIP2) stabilizes the open state of KATP channels without affecting single-channel current amplitude (3235). Open time distributions are not strongly affected by addition of ATP or PIP2, but rather the probability of being in either a closed or open state is altered (36, 37). After application of PIP2 to excised inside-out membrane patches, [ATP]-response curves are shifted rightward, indicating a decrease in ATP-sensitivity (38, 39). A plot of Po against the half-maximal inhibitory concentration of ATP (K1/2,ATP) (Fig. 2A) reveals a common trajectory between patches after the application of PIP2, indicating that Po and K1/2,ATP are strongly correlated (37, 39), and the vast majority of KATP mutations described support this hypothesis. Recently, however, disease-related mutations in SUR1 have been found that show decreased channel activity together with decreased ATP sensitivity (40), suggesting that the modulation of Kir6.2 by SUR1 may be altered as to deviate from the model.

Figure 2
Relationship between channel open probability (Po) and K1/2,ATP and kinetic model for channel gating. A: As the channel Po increases, by increasing membrane PIP2 or with open state stabilizing mutations, the K1/2,ATP also increases reproducibly along ...

Kinetic Models of Activation and Inhibition Describe KATP Channel Gating

KATP channel gating is effectively described by assuming that all four Kir6.2 subunits undergo independent ‘activating’ transitions (1) and that the channel is in a conducting state only when all four subunits are in the active conformation. Thus, ‘deactivation’ of one subunit is sufficient to render the channel nonconductive. Four independent, noncooperative subunits result in a steep [ATP] dependence of channel inhibition.

As in other Kir channels, KATP channels undergo intraburst transitions that are modulated by the structure of the selectivity filter. Conversely, there are also multiple, longer closed inter-burst intervals which are modulated by ligand action on the channel (39). Thus, channel gating can be modeled by a kinetic scheme with a single major open state and multiple ligand-dependent and -independent closed states (Fig. 2B).

Such models predict the strong correlation between K1/2,ATP and Po by linking the open state and ATP-dependent closed state to a common ligand-independent closed state (39). As the equilibrium is shifted towards the open state, such as by the addition of PIP2, channel occupancy of the ligand-independent closed state decreases. This, in turn, reduces the accessibility of ATP to the closed state and results in a decrease in apparent ATP-sensitivity (36, 37, 39).


Glucose Sensing and Insulin Secretion

KATP channels serve as glucose sensors and effectively initiate the glucose stimulated insulin secretion (GSIS) pathway (Fig. 3) (14, 41). Glucose enters β-cells via the glucose transporter GLUT2 and is broken down through cytoplasmic glycolytic pathways. Pyruvate then proceeds to the citric acid cycle, leading to the generation of ATP and fall of ADP, which in turn deactivates KATP channels. As KATP channels close, the cell membrane tends to depolarize, leading to opening of voltage gated calcium channels, influx of calcium, and Ca2+-dependent secretion of insulin granules (42). Hence, pancreatic KATP channels are biological sensors of blood sugars, linking glucose levels to insulin secretion by modulating membrane excitability.

Figure 3
The glucose stimulated insulin secretion (GSIS) pathway in the pancreatic β-cell. An increase in the intracellular ratio of [ATP] to [ADP] will inhibit KATP channels, leading to membrane depolarization. The increase in membrane potential activates ...

Aberrant Function Leads to Disease: Molecular Perspective on ND and HI

Unlike cardiac KATP channels, pancreatic KATP channels are constitutively active, due in part to the enhanced stimulatory effects conferred by SUR1 (versus SUR2A) (31) as well as to the relatively low [ATP]/[ADP] in β-cells during fasting. Because of the critical role that these channels play in GSIS, mutations that lead to aberrant channel function have the potential to cause a broad spectrum of insulin secreting disorders and numerous mutations which alter pancreatic KATP channel function have now been implicated in disease (4, 41, 43). KATP mutations that decrease channel currents have been found in patients with congenital hyperinsulinism (HI), characterized by inappropriate levels of insulin secretion leading to hypoglycemia (42). These mutations tend to fall into two categories: those which reduce MgADP stimulation of the channel and those which partially or entirely abrogate channel cell-surface expression (42, 44). Recently, a subset of mutations which alter channel stability has been found to occur in HI. These mutations disrupt the interface of the four pore-forming Kir6.2 subunits and result in channel inactivation (4547). In addition, an HI-related mutation in Kir6.2 has been shown to decrease the intrinsic open probability of the channel (48).

On the other hand, mutations that increase KATP channel activity lead to a persistent hyperpolarized state which, depending on the extent of overactivity, may negate the inhibitory effects of metabolism, leading to diabetes. More specifically, neonatal diabetes falls into two major clinical subtypes, permanent neonatal diabetes mellitus (PNDM) and transient neonatal diabetes mellitus (TNDM), both defined by insulin-requiring hyperglycemia within the first 3 months of life (49). Typically, these diabetes mutations act functionally either by decreasing channel sensitivity to ATP, by increasing the ATP-independent open probability (Po) of the channel complex, or by enhancing MgADP stimulation. The most severe permanent form of the disease extends beyond the pancreas to neuronal or other tissues, such that patients experience motor and intellectual developmental delay, epilepsy, and neonatal diabetes (DEND). The extrapancreatic symptoms of DEND have been attributed to KATP overactivity in muscle and/or nerves and brain (50, 51), highlighting the systemic role of Kir6.2 and SUR1 in tissues outside the pancreas. For a thorough and updated catalog of reported mutations found in Kir6.2 and SUR1 subunits of pancreatic KATP channels, consult (17).

Animal Models and KATP Blocker Therapy in Neonatal and Adult Diabetes

The role of overactive KATP channels in the etiology of neonatal diabetes was elucidated in 2000 with the generation of transgenic mice models expressing overactive KATP channels (52) and has since been confirmed by inducible transgenic mice models (53, 54). Sulfonylureas (SUs) act by blocking KATP channels, leading to depolarization and insulin secretion, and have been long-standing therapeutic agents for the treatment of type-2 diabetes. However, patients presenting with hyperglycemia within the first 3 months of life were uniformly treated with insulin, since the cause of neonatal diabetes remained unknown. The realization that activating mutations in KATP genes do in fact lead to neonatal diabetes in humans (55) presented a novel treatment avenue. To determine the efficacy and safety of SU therapy for the treatment of neonatal diabetes, clinical studies have been performed in which patients with activating KATP mutations have been switched from insulin to oral SUs. In early studies (56), 90% of patients transitioned successfully and SUs have since become the preferred treatment option for neonatal diabetes.


KATP channels are widespread in visceral and vascular smooth muscle (57). Among the former, KATP channels have been found in pig urethra (5860); rodent colon (61) and stomach (62); and human myometrium (63, 64), corpus cavernosum (65), and prostate (66); and in all these tissues they modulate contraction and muscular tone. Most attention, however, has been drawn to KATP channels in the vasculature, because of their ability to control arterial diameter and their potential in the treatment of hypertension and other vascular contractility disorders (67). KATP channels are intrinsically involved in the association between cell metabolism, extracellular [K+], and tissue perfusion demands. It has been reported that hypotension associated with septic shock and hypoxia-induced lactic acidosis is reversible with the administration of the sulfonylurea glibenclamide (68). This suggests that activation of KATP channels by products of anaerobic metabolism such as lactic acid contribute to widespread vasodilatation, which may ensure perfusion to the brain and heart following an ischemic challenge (69). Vasodilators like adenosine, calcitonin gene-related peptide, prostacyclin, and β-agonists have been shown to increase native KATP channel activity in vascular smooth muscle preparations by means of cAMP-dependent PKA activation (7072), and this is thought to decrease contractility by hyperpolarizing the cell membrane and reducing Ca2+ influx. Conversely, vasoconstrictors such as angiotensin II, endothelin-I, and vasopressin activate PKC pathways that block vascular KATP channels, which results in membrane depolarization, Ca2+ entry into the cell, and smooth muscle contraction (69, 73).

Precise identification of the molecular constituents of the KATP channels in each tissue is necessary for the rational design of drugs targeted to specific organs. This is especially challenging in smooth muscle, where different combinations of Kir6.x and SURx have been described (61, 62, 74), and coexistence of mixed KATP channel populations in the same tissue (58, 73, 75) and even heteromerization between Kir6.1 and Kir6.2 (26, 76) may occur. In the vasculature, two main KATP channel subtypes have been described, based on unitary conductance, sensitivity to nucleotides, and pharmacology (67). One of them, the medium conductance (50–70 pS) KATP channel, functionally resembles KATP channels in cardiomyocytes (75), although the molecular identity remains unclear. The predominant subtype of vascular KATP channel, however, is the low conductance (20–50 pS) KNDP channel. Unlike their classic pancreatic or cardiac counterparts, KNDP channels are not spontaneously activated in absence of nucleotides; in addition, they are inhibited by intra-cellular ATP, but at higher concentrations than KATP channels in β-cells or cardiac myocytes (61, 77, 78). These properties are mimicked by recombinant Kir6.1/SUR2B channels (7981), indicating that vascular KNDP channels are likely formed by this subunit combination. Native KNDP and recombinant Kir6.1/SUR2B channels are activated by diazoxide in the absence of intracellular MgADP, unlike SUR1- and SUR2A-containing channels (82), and exhibit higher sensitivity to glibenclamide than Kir6.2/SUR2B channels (83). Mice deficient in Kir6.1, but not Kir6.2, lack vascular KATP channels and display symptoms of Prinzmetal’s angina, i.e., myocardial ischemia and coronary vasospasm leading to sudden death (8486), providing further evidence for Kir6.1 involvement in vascular KATP channel function and regulation.


KATP channels are expressed at high density in the membrane of cardiomyocytes, but do not seem to contribute to normal myocardial contractility, and instead serve a protective purpose. Thus, sarcolemmal KATP channels remain closed under basal conditions (87, 88), and activate under metabolic stress, as in anoxia, metabolic inhibition, or ischemia, which leads to shortening of the action potential, reduction of calcium entry, and contractile failure. This confers protection to the myocardium, as it prevents Ca2+ overload and excessive contraction, helping preserve energy, and accelerating recovery after an ischemic event (86, 89, 90). Although cardioprotection after a severe metabolic challenge has been convincingly linked to activation of sarcolemmal KATP channels (91), KATP function in less stressful physiological conditions is still a matter of debate. For example, one study indicates that exercise or stress may be sufficient to activate KATP channels in the heart (92). Most studies, however, have been devoted to ascertaining the role of sarcolemmal KATP channels in cardiac rhythm, with conflicting results. Treatment with KATP channel openers has been shown to stabilize the resting membrane potential and reduce the frequency of arrhythmias in some studies (93), but has proven proarrhythmic in others (2, 94). Similarly, both increased (95) and decreased (94, 96) incidence of tachycardia and ventricular fibrillation following treatment with glibenclamide have been reported.

Until recently, most functional, pharmacological and biophysical evidence supported the view that cardiac sarcolemmal KATP channels are heteromultimers of Kir6.2 and SUR2A (9799). To date, the model holds true for Kir6.2: whereas Kir6.1 is also present in the heart, and has been shown to coassemble with Kir6.2 to form functionally active channels in vitro (76, 100), Kir6.2 seems to be the physiologically relevant Kir subunit in the sarcolemma: Kir6.2-deficient mice are devoid of cardiac KATP channels, show lack of cardioprotection during ischemia, and are intolerant of vigorous exercise (86). On the other hand, SUR1 transcripts and protein have been found in the heart (101, 102), and SUR2A−/− mice retain some cardiac KATP channel activity (103). It has now been demonstrated that the make-up of cardiac sarcolemmal KATP channels is regionally heterogeneous: while SUR2A is an essential component in the ventricle, atrial KATP channels are formed by the association of Kir6.2 and SUR1, at least in the mouse (104). Advances in understanding pathology associated with cardiac KATP channels have been limited by the scarcity of naturally occurring heart disease-causing mutations in their molecular constituents: none of the mutations in the Kir6.2 and SUR1 genes that result in altered insulin secretion in the pancreas (44, 55, 105), and none of the known polymorphisms of Kir6.2 (106), have been linked to cardiac dysfunction. On the other hand, two mutations in the second nucleotide binding domain of SUR2 are reported to underlie human dilated cardiomyopathy, by rendering sarcolemmal KATP channels less sensitive to inhibition by ATP and activation by ADP (107).


As a coupler of cellular energetics to membrane excitability, KATP channels sense and transmit changes in intracellular metabolism to the surface of the cell, leading to both local morphological changes (such as adjustment in muscle tone) and distantly acting signaling sequences (such as the secretion of insulin). The diversity of KATP channel properties, resulting from differential molecular makeup, allows for exploitation by differential pharmacology, leading to tissue-targeted drugs. As further insights into the structure and function of KATP channels are made, new advances will be made into the treatment of diseases as diverse as cardiac arrhythmias and type-2 diabetes.


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