Sulfonylurea receptor
| ATP-binding cassette, sub-family C (CFTR/MRP), member 8 | |
|---|---|
| Identifiers | |
| Symbol | ABCC8 |
| Alt. symbols | SUR1 |
| Entrez | 6833 |
| HUGO | 59 |
| OMIM | 600509 |
| RefSeq | NM_000352 |
| UniProt | Q09428 |
| Other data | |
| Locus | Chr. 11 p15.1 |
| ATP-binding cassette, sub-family C (CFTR/MRP), member 9 | |
|---|---|
| Identifiers | |
| Symbol | ABCC9 |
| Alt. symbols | SUR2A, SUR2B |
| Entrez | 10060 |
| HUGO | 60 |
| OMIM | 601439 |
| RefSeq | NM_005691 |
| UniProt | O60706 |
| Other data | |
| Locus | Chr. 12 p12.1 |
In the field of 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]
There are three forms of the sulfonylurea receptor, SUR1 encoded by the ABCC8 gene and SUR2A and SUR2B which are splice variants arising from a single ABCC9 gene.[3]
Function
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 down stream 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 increase in membrane potential 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]
Tissue distribution
The isoforms of the sulfonylurea receptor have the following tissue distribution:
- adipose tissue - SUR2B/Kir6.1
- pancreatic beta cells - SUR1/Kir6.2
- cardiac myocytes - SUR2A
- skeletal muscle - SUR2A
- smooth muscle - SUR2B
- brain - SUR1, SUR2A and SUR2B [5][6]
Disease linkage
The SUR1 protein is coded by the ABCC8 gene and is associated with congenital hyperinsulinism[8] and susceptibility to type 2 diabetes.[9]
References
- ↑ Campbell, J. D.; Sansom, M. S.; Ashcroft, F. M. (2003). "Potassium channel regulation". EMBO Reports 4 (11): 1038–42. doi:10.1038/sj.embor.embor7400003. PMC 1326373. PMID 14593442.
- ↑ sulfonylurea receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
- ↑ Aguilar-Bryan L, Clement JP 4th, Gonzalez G, Kunjilwar K, Babenko A, Bryan J (1 January 1998). "Toward understanding the assembly and structure of KATP channels". Physiol Rev 78 (1): 227–45. PMID 9457174.
- ↑ Nichols, C. G. (2006). "KATP channels as molecular sensors of cellular metabolism". Nature 440 (7083): 470–6. doi:10.1038/nature04711. PMID 16554807.
- 1 2 Simard JM, Woo SK, Schwartzbauer GT, Gerzanich V (June 2012). "Sulfonylurea receptor 1 in central nervous system injury: A focused review". J Cereb Blood Flow Metab 32 (9): 1699–1717. doi:10.1038/jcbfm.2012.91. PMC 3434627. PMID 22714048.
- 1 2 3 Ortega, F. J.; Gimeno-Bayon, J; Espinosa-Parrilla, J. F.; Carrasco, J. L.; Batlle, M; Pugliese, M; Mahy, N; Rodríguez, M. J. (2012). "ATP-dependent potassium channel blockade strengthens microglial neuroprotection after hypoxia-ischemia in rats". Experimental Neurology 235 (1): 282–96. doi:10.1016/j.expneurol.2012.02.010. PMID 22387180.
- ↑ Simard, J. M.; Chen, M; Tarasov, K. V.; Bhatta, S; Ivanova, S; Melnitchenko, L; Tsymbalyuk, N; West, G. A.; Gerzanich, V (2006). "Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke". Nature Medicine 12 (4): 433–40. doi:10.1038/nm1390. PMC 2740734. PMID 16550187.
- ↑ Fournet, J. C.; Junien, C (2004). "Genetics of congenital hyperinsulinism". Endocrine pathology 15 (3): 233–40. PMID 15640549.
- ↑ Reis, A. F.; Velho, G (2002). "Sulfonylurea receptor -1 (SUR1): Genetic and metabolic evidences for a role in the susceptibility to type 2 diabetes mellitus". Diabetes & metabolism 28 (1): 14–9. PMID 11938023.
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