| potassium inwardly-rectifying channel, subfamily J, member 8 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | KCNJ8 | ||||||
| Alt. symbols | Kir6.1 | ||||||
| NCBI gene | 3764 | ||||||
| HGNC | 6269 | ||||||
| OMIM | 600935 | ||||||
| RefSeq | NM_004982 | ||||||
| UniProt | Q15842 | ||||||
| Other data | |||||||
| Locus | Chr. 12p12.1 | ||||||
| |||||||
| potassium inwardly-rectifying channel, subfamily J, member 11 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | KCNJ11 | ||||||
| Alt. symbols | Kir6.2 | ||||||
| NCBI gene | 3767 | ||||||
| HGNC | 6257 | ||||||
| OMIM | 600937 | ||||||
| RefSeq | NM_000525 | ||||||
| UniProt | Q14654 | ||||||
| Other data | |||||||
| Locus | Chr. 11p15.1 | ||||||
| |||||||
| ATP-binding cassette, sub-family C (CFTR/MRP), member 8 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | ABCC8 | ||||||
| Alt. symbols | SUR1 | ||||||
| NCBI gene | 6833 | ||||||
| HGNC | 59 | ||||||
| OMIM | 600509 | ||||||
| RefSeq | NM_000352 | ||||||
| UniProt | Q09428 | ||||||
| Other data | |||||||
| Locus | Chr. 11p15.1 | ||||||
| |||||||
| ATP-binding cassette, sub-family C (CFTR/MRP), member 9 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | ABCC9 | ||||||
| Alt. symbols | SUR2A, SUR2B | ||||||
| NCBI gene | 10060 | ||||||
| HGNC | 60 | ||||||
| OMIM | 601439 | ||||||
| RefSeq | NM_005691 | ||||||
| UniProt | O60706 | ||||||
| Other data | |||||||
| Locus | Chr. 12p12.1 | ||||||
| |||||||
AnATP-sensitive potassium channel (or KATP channel) is a type ofpotassium channel that is gated by intracellularnucleotides,ATP andADP. ATP-sensitive potassium channels are composed of Kir6.x-type subunits andsulfonylurea receptor (SUR) subunits, along with additional components.[1] KATP channels are widely distributed inplasma membranes;[2] however some may also be found on subcellular membranes. These latter classes of KATP channels can be classified as being eithersarcolemmal ("sarcKATP"),mitochondrial ("mitoKATP"), ornuclear ("nucKATP").
KATP channels were first identified incardiac myocytes byAkinori Noma in Japan.[3] Glucose-regulated KATP channel activity was found in pancreatic beta cells byFrances Ashcroft at theUniversity of Oxford.[4] The closure of KATP channels leads to increased insulin secretion in beta cells and reduces glucagon secretion in alpha cells.[5]
SarcKATP are composed of eight protein subunits (octamer). Four of these are members of theinward-rectifier potassium ion channel family Kir6.x (eitherKir6.1 orKir6.2), while the other four are sulfonylurea receptors (SUR1,SUR2A, andSUR2B).[6] The Kir subunits have two transmembrane spans and form the channel's pore. The SUR subunits have three additional transmembrane domains, and contain two nucleotide-binding domains on the cytoplasmic side.[7] These allow for nucleotide-mediated regulation of the potassium channel, and are critical in its roles as a sensor of metabolic status. These SUR subunits are also sensitive to sulfonylureas, MgATP (themagnesium salt of ATP), and some other pharmacological channel openers. While all sarcKATP are constructed of eight subunits in this 4:4 ratio, their precise composition varies with tissue type.[8]
MitoKATP were first identified in 1991 by single-channel recordings of the inner mitochondrial membrane.[9] The molecular structure of mitoKATP is less clearly understood than that of sarcKATP. Some reports indicate that cardiac mitoKATP consist of Kir6.1 and Kir6.2 subunits, but neither SUR1 nor SUR2.[10][11] More recently, it was discovered that certain multiprotein complexes containing succinate dehydrogenase can provide activity similar to that of KATP channels.[12]
The presence of nucKATP was confirmed by the discovery that isolated patches of nuclear membrane possess properties, both kinetic and pharmacological, similar toplasma membrane KATP channels.[13]
Fourgenes have been identified as members of the KATP gene family. Thesur1 andkir6.2 genes are located in chr11p15.1 whilekir6.1 andsur2 genes reside in chr12p12.1. Thekir6.1 andkir6.2 genes encode the pore-forming subunits of the KATP channel, with the SUR subunits being encoded by thesur1 (SUR1) gene or selective splicing of thesur2 gene (SUR2A and SUR2B).[14]
Changes in thetranscription of these genes, and thus the production of KATP channels, are directly linked to changes in the metabolic environment. Highglucose levels, for example, induce a significant decrease in thekir6.2 mRNA level – an effect that can be reversed by lower glucose concentration.[15] Similarly, 60 minutes ofischemia followed by 24 to 72 hours of reperfusion leads to an increase inkir6.2 transcription in left ventricle rat myocytes.[16]
A mechanism has been proposed for the cell's KATP reaction tohypoxia and ischemia.[17] Low intracellular oxygen levels decrease the rate of metabolism by slowing theTCA cycle in the mitochondria. Unable to transfer electrons efficiently, the intracellularNAD+/NADH ratio decreases, activating phosphotidylinositol-3-kinase and extracellular signal-regulated kinases. This, in turn, upregulatesc-jun transcription, creating a protein which binds to thesur2promoter.[citation needed]
One significant implication of the link between cellularoxidative stress and increased KATP production is that overall potassium transport function is directly proportional to the membrane concentration of these channels. In cases ofdiabetes, KATP channels cannot function properly, and a marked sensitivity to mild cardiac ischemia and hypoxia results from the cells' inability to adapt to adverse oxidative conditions.[18]
The degree to which particular compounds are able to regulate KATP channel opening varies with tissue type, and more specifically, with a tissue's primary metabolic substrate.
Inpancreaticbeta cells, ATP is the primary metabolic source, and the ATP/ADP ratio determines KATP channel activity. Under resting conditions, the weaklyinwardly rectifying KATP channels in pancreatic beta cells are spontaneously active, allowing potassium ions to flow out of the cell and maintaining a negativeresting membrane potential (slightly more positive than the K+reversal potential).[19] In the presence of higher glucose metabolism, and consequently increased relative levels of ATP, the KATP channels close, causing the membrane potential of the cell todepolarize, activatingvoltage-gated calcium channels, and thus promoting the calcium-dependentrelease ofinsulin.[19] The change from one state to the other happens quickly and synchronously, due toC-terminus multimerization among proximate KATP channel molecules.[20]
Cardiomyocytes, on the other hand, derive the majority of their energy from long-chainfatty acids and their acyl-CoA equivalents. Cardiac ischemia, as it slows the oxidation of fatty acids, causes an accumulation of acyl-CoA and induces KATP channel opening while free fatty acids stabilize its closed conformation. This variation was demonstrated by examiningtransgenic mice, bred to have ATP-insensitive potassium channels. In the pancreas, these channels were always open, but remained closed in the cardiac cells.[21][22]
Upon the onset of a cellular energy crisis, mitochondrial function tends to decline. This is due to alternating innermembrane potential, imbalanced trans-membraneion transport, and an overproduction offree radicals, among other factors.[8] In such a situation, mitoKATP channels open and close to regulate both internal Ca2+ concentration and the degree of membrane swelling. This helps restore proper membrane potential, allowing further H+ outflow, which continues to provide the proton gradient necessary for mitochondrial ATP synthesis. Without aid from the potassium channels, the depletion of high energy phosphate would outpace the rate at which ATP could be created against an unfavorableelectrochemical gradient.[23]
Nuclear and sarcolemmal KATP channels also contribute to the endurance of and recovery from metabolic stress. In order to conserve energy, sarcKATP open, reducing the duration of theaction potential while nucKATP-mediated Ca2+ concentration changes within the nucleus favor the expression of protective protein genes.[8]
Cardiac ischemia, while not always immediately lethal, often leads to delayed cardiomyocyte death bynecrosis, causing permanent injury to the heart muscle. One method, first described by Keith Reimer in 1986, involves subjecting the affected tissue to brief, non-lethal periods of ischemia (3–5 minutes) before the major ischemic insult. This procedure is known asischemic preconditioning ("IPC"), and derives its effectiveness, at least in part, from KATP channel stimulation.[citation needed]
Both sarcKATP and mitoKATP are required for IPC to have its maximal effects. Selective mitoKATP blockade with 5-hydroxydecanoic acid ("5-HD") or MCC-134[24] completely inhibits the cardioprotection afforded by IPC, andgenetic knockout of sarcKATP genes[25] in mice has been shown to increase the basal level of injury compared to wild type mice. This baseline protection is believed to be a result of sarcKATP's ability to prevent cellular Ca2+ overloading and depression of force development during muscle contraction, thereby conserving scarce energy resources.[26]
Absence of sarcKATP, in addition to attenuating the benefits of IPC, significantly impairs the myocyte's ability to properly distribute Ca2+, decreasing sensitivity tosympathetic nerve signals, and predisposing the subject toarrhythmia and sudden death.[27] Similarly, sarcKATP regulates vascularsmooth muscle tone, and deletion of thekir6.2 orsur2 genes leads tocoronary arteryvasospasm and death.[28]
Upon further exploration of sarcKATP's role incardiac rhythm regulation, it was discovered that mutant forms of the channel, particularly mutations in the SUR2 subunit, were responsible fordilated cardiomyopathy, especially after ischemia/reperfusion.[29] It is still unclear as to whether opening of KATP channels has completely pro- or antiarrhythmic effects. Increased potassium conductance should stabilize membrane potential during ischemic insults, reducing the extent infarct andectopic pacemaker activity. On the other hand, potassium channel opening acceleratesrepolarization of the action potential, possibly inducing arrhythmic reentry.[8]
ATP-sensitivepotassium channel openers includingminoxidil (via itsactive metaboliteminoxidil sulfate),diazoxide, andpinacidil are associated withhypertrichosis in humans.[30][31][32] Other ATP-sensitive potassium channel openers, likecromakalin andP-1075 (ananalogue of pinacidil), stimulate hair growth in baldingstump-tailed macaques, although another ATP-sensitive potassium channel opener,RP-49356, was not efficacious.[30][31][32] The ATP-sensitive potassium channel openersnaminidil (BMS-234303) and P-1075 were under formal development for treatment ofhair loss and reachedphase 2clinical trials for this indication but were never marketed.[33][34][35] Minoxidil also has other actions, and it is not fully clear whether opening of ATP-sensitive potassium channels is responsible for the hair growth-stimulatory effects of minoxidil and other ATP-sensitive potassium channel openers.[30][31][32] In any case, KATP channel activation via minoxidil and other agents has been found to directly stimulate follicular growth incultured hair folliclesex vivo.[36][37] This can be reversed by the KATP inhibitortolbutamide.[37] In addition,Cantú syndrome, which involvesgain-of-functionmutations in KATP channelsubunits (specificallySUR2 andKIR6.1), is associated with hypertrichosis.[36][37]
Other potassium channel openers, like diazoxide [39, 40] and pinacidil [41] can cause hypertrichosis in humans as well as minoxidil. In balding macaques minoxidil, cromakalin and P-1075 (a pinacidil analogue) stimulate hair growth in about 20 weeks of topical treatment, whereas a fourth potassium channel opener, called RP49356, is not effective [42].
The evidence that [potassium channel openers (PCOs)] are active on hair growth is correlative. In humans three PCOs have been reported to affect hair growth. Minoxidil was reported to induce hypertrichosis during early clinical trials as an antihypertensive [12]. These side effects were characterized by increasingly visual facial hair, thickening of eyebrows, and diffuse hair growth across the upper back and limbs. Systemic minoxidil induced hypertrichosis in 80–100% of adults [13]. Clinical trials using topical minoxidil demonstrate increased scalp hair in about 39% of treated balding men. Oral diazoxide causes hypertrichosis in most hypoglycemic children and about 1% of adults, and induces some scalp hair in 25% of the balding patients [13–15]. Systemic pinacidil induces hypertrichosis in 2–13% of patients [13]. We are not aware of any topical hair growth trials using pinacidil.
Through its vasodilatory properties [19], minoxidil may enhance blood flow to the scalp, improving oxygen and nutrient delivery to hair follicles, and creating a microenvironment conducive to hair growth [20]. However, studies of organ-cultured hair follicles, which lack a vascular supply, have shown that minoxidil directly stimulates follicular growth via activation of KATP channels in dermal papilla cells [21]. This finding suggests that while vasodilation may contribute to minoxidil's mechanism of action, KATP channel activation is primarily responsible mechanistically. The clinical relevance of this pathway is further supported by Cantu syndrome, in which gain-of-function mutations in KATP channel subunits (SUR2 and KIR6.1) cause hypertrichosis [22].
As mentioned earlier, the hair-growth-promoting properties of minoxidil were clear from initial development. [...] Of concern, if excessive doses are used, even topically, there is the potential for minoxidil to have systemic effects—precipitating a possible "drug-induced Cantú syndrome." Indeed [pulmonary hypertension (PH)], edema, coarsening of facial features, and even reopening of the ductus arteriosus are associated with the Kir6.1/SUR2B active [potassium channel openers (KCOs)] minoxidil and diazoxide (156–158). Multiple KCOs induce and prolong anagen, the rapidly dividing stage of hair, in cultured follicles to promote growth, which can be reversed by the KATP inhibitor tolbutamide (86–88, 159). It is possible that CS-associated mutations have the same hair growth cycle effects, though this requires clarification. Thinking more broadly about the electrical consequences, KATP activation versus voltage-gated calcium channel (VGCC) activation would be expected to have opposing electrophysiological effects, and interestingly Timothy syndrome, caused by gain-of-function mutations in the VGCC, CaV1.2 is associated with baldness at birth (160), potentially the reverse mechanistic phenomenon.