ATP-binding cassette, subfamily C (CFTR/MRP), member 8 | |||||||
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Identifiers | |||||||
Symbol | ABCC8 | ||||||
Alt. symbols | SUR1 | ||||||
NCBI gene | 6833 | ||||||
HGNC | 59 | ||||||
OMIM | 600509 | ||||||
RefSeq | NM_000352 | ||||||
UniProt | Q09428 | ||||||
Other data | |||||||
Locus | Chr. 11 p15.1 | ||||||
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ATP-binding cassette, subfamily C (CFTR/MRP), member 9 | |||||||
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Identifiers | |||||||
Symbol | ABCC9 | ||||||
Alt. symbols | SUR2A, SUR2B | ||||||
NCBI gene | 10060 | ||||||
HGNC | 60 | ||||||
OMIM | 601439 | ||||||
RefSeq | NM_005691 | ||||||
UniProt | O60706 | ||||||
Other data | |||||||
Locus | Chr. 12 p12.1 | ||||||
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In molecular biology, the sulfonylurea receptors (SUR) are membrane proteins which are the molecular targets of the sulfonylurea class of antidiabetic drugs whose mechanism of action is to promote insulin release from pancreatic beta cells. More specifically, SUR proteins are subunits of the inward-rectifier potassium ion channels Kir6.x (6.1 and 6.2). [1] The association of four Kir6.x and four SUR subunits form an ion conducting channel commonly referred to as the KATP channel. [2]
Three forms of the sulfonylurea receptor are known, SUR1 encoded by the ABCC8 gene, and SUR2A and SUR2B, which are splice variants arising from a single ABCC9 gene. [3]
The primary function of the sulfonylurea receptor is to sense intracellular levels of the nucleotides ATP and ADP and in response facilitate the open or closing its associated Kir6.x potassium channel. Hence, the KATP channel monitors the energy balance within the cell. [4]
Depending on the tissue in which the KATP channel is expressed, altering the membrane potential can trigger a variety of downstream events. For example, in pancreatic beta cells, high levels of glucose lead to increased production of ATP, which, in turn, binds to the KATP channel resulting in channel closure. The relative depolarization (decrease in membrane hyperpolarization), in turn, opens voltage-dependent calcium channels increasing intracellular calcium concentrations, which triggers exocytosis of insulin.
Under cerebral ischemic conditions, SUR1, the regulatory subunit of the KATP and the NCCa-ATP channels, is expressed in neurons, astrocytes, oligodendrocytes, endothelial cells [5] and by reactive microglia. [6] Blockade of SUR1 receptors with glibenclamide has been involved in improved outcome in animal stroke models and investigational human studies by preventing brain swelling [7] and enhancing neuroprotection. [6]
The isoforms of the sulfonylurea receptor have the following tissue distribution:
The SUR1 protein is coded by the ABCC8 gene and is associated with congenital hyperinsulinism [8] and susceptibility to type 2 diabetes. [9]
Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are diminished, leading to insufficient insulin secretion and hyperglycemia.
Congenital hyperinsulinism (HI or CHI) is a rare condition causing severe hypoglycemia in newborns due to the overproduction of insulin. There are various causes of HI, some of which are known to be the result of a genetic mutation. Sometimes HI occurs on its own (isolated) and more rarely associated with other medical conditions.
Glibenclamide, also known as glyburide, is an antidiabetic medication used to treat type 2 diabetes. It is recommended that it be taken together with diet and exercise. It may be used with other antidiabetic medication. It is not recommended for use by itself in type 1 diabetes. It is taken by mouth.
Acetohexamide is a first-generation sulfonylurea medication used to treat diabetes mellitus type 2, particularly in people whose diabetes cannot be controlled by diet alone.
Inward-rectifier potassium channels (Kir, IRK) are a specific lipid-gated subset of potassium channels. To date, seven subfamilies have been identified in various mammalian cell types, plants, and bacteria. They are activated by phosphatidylinositol 4,5-bisphosphate (PIP2). The malfunction of the channels has been implicated in several diseases. IRK channels possess a pore domain, homologous to that of voltage-gated ion channels, and flanking transmembrane segments (TMSs). They may exist in the membrane as homo- or heterooligomers and each monomer possesses between 2 and 4 TMSs. In terms of function, these proteins transport potassium (K+), with a greater tendency for K+ uptake than K+ export. The process of inward-rectification was discovered by Denis Noble in cardiac muscle cells in 1960s and by Richard Adrian and Alan Hodgkin in 1970 in skeletal muscle cells.
Meglitinides or glinides are a class of drugs used to treat type 2 diabetes.
An ATP-sensitive potassium channel is a type of potassium channel that is gated by intracellular nucleotides, ATP and ADP. ATP-sensitive potassium channels are composed of Kir6.x-type subunits and sulfonylurea receptor (SUR) subunits, along with additional components. KATP channels are found in the plasma membrane; however some may also be found on subcellular membranes. These latter classes of KATP channels can be classified as being either sarcolemmal ("sarcKATP"), mitochondrial ("mitoKATP"), or nuclear ("nucKATP").
The glucagon-like peptide-1 receptor (GLP1R) is a receptor protein found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of G protein-coupled receptors. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.
Kir6.2 is a major subunit of the ATP-sensitive K+ channel, a lipid-gated inward-rectifier potassium ion channel. The gene encoding the channel is called KCNJ11 and mutations in this gene are associated with congenital hyperinsulinism.
ATP-binding cassette transporter sub-family C member 8 is a protein that in humans is encoded by the ABCC8 gene. ABCC8 orthologs have been identified in all mammals for which complete genome data are available.
G protein-activated inward rectifier potassium channel 2 is a protein that in humans is encoded by the KCNJ6 gene. Mutation in KCNJ6 gene has been proposed to be the cause of Keppen-Lubinsky Syndrome (KPLBS).
Potassium inwardly-rectifying channel, subfamily J, member 8, also known as KCNJ8, is a human gene encoding the Kir6.1 protein. A mutation in KCNJ8 has been associated with cardiac arrest in the early repolarization syndrome.
G protein-activated inward rectifier potassium channel 4(GIRK-4) is a protein that in humans is encoded by the KCNJ5 gene and is a type of G protein-gated ion channel.
Alpha-endosulfine is a protein that in humans is encoded by the ENSA gene.
ATP-binding cassette, sub-family C member 9 (ABCC9) also known as sulfonylurea receptor 2 (SUR2) is an ATP-binding cassette transporter that in humans is encoded by the ABCC9 gene.
Neonatal diabetes mellitus (NDM) is a disease that affects an infant and their body's ability to produce or use insulin.NDM is a kind of diabetes that is monogenic and arises in the first 6 months of life. Infants do not produce enough insulin, leading to an increase in glucose accumulation. It is a rare disease, occurring in only one in 100,000 to 500,000 live births. NDM can be mistaken for the much more common type 1 diabetes, but type 1 diabetes usually occurs later than the first 6 months of life. There are two types of NDM: permanent neonatal diabetes mellitus (PNDM), a lifelong condition, and transient neonatal diabetes mellitus (TNDM), a form of diabetes that disappears during the infant stage but may reappear later in life.
The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.
HMR 1883 and its sodium salt HMR 1098, are experimental anti-arrhythmic drugs classified as sulfonylthiourea compounds. Their main purpose is to treat ventricular fibrillation caused by myocardial ischemia. They were synthesized via structural modifications to glibenclamide, an antidiabetic drug. Both HMR 1883 and glibenclamide act by inactivating the ATP-sensitive potassium channels (KATP) responsible for potassium efflux. Unlike glibenclamide, HMR 1883 has been suggested to target selectively the Kir6.2/SUR2A KATP subtype, found mostly in the membranes of cardiac cells. However, data showing that HMR 1098 inhibits the Kir6.2/SUR1 KATP subtype found in insulin-secreting pancreatic beta cells challenges this view.
Guangxitoxin, also known as GxTX, is a peptide toxin found in the venom of the tarantula Plesiophrictus guangxiensis. It primarily inhibits outward voltage-gated Kv2.1 potassium channel currents, which are prominently expressed in pancreatic β-cells, thus increasing insulin secretion.
Colin G. Nichols FRS is the Carl Cori Endowed Professor, and Director of the Center for Investigation of Membrane Excitability Diseases at Washington University in St. Louis, Missouri.