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]
| ATP-binding cassette, subfamily 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. 11 p15.1 | ||||||
| |||||||
| ATP-binding cassette, subfamily 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. 12 p12.1 | ||||||
| |||||||
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]
Function
editThe 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]
Tissue distribution
editThe 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
editThe SUR1 protein is coded by the ABCC8 gene and is associated with congenital hyperinsulinism[8] and susceptibility to type 2 diabetes.[9]
References
edit- ^ Campbell JD, Sansom MS, Ashcroft FM (November 2003). "Potassium channel regulation". EMBO Reports. 4 (11): 1038–42. doi:10.1038/sj.embor.embor7400003. PMC 1326373. PMID 14593442.
- ^ sulfonylurea+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- ^ Aguilar-Bryan L, Clement JP, Gonzalez G, Kunjilwar K, Babenko A, Bryan J (January 1998). "Toward understanding the assembly and structure of KATP channels". Physiological Reviews. 78 (1): 227–45. doi:10.1152/physrev.1998.78.1.227. PMID 9457174. S2CID 11851627.
- ^ Nichols CG (March 2006). "KATP channels as molecular sensors of cellular metabolism". Nature. 440 (7083): 470–6. Bibcode:2006Natur.440..470N. doi:10.1038/nature04711. PMID 16554807. S2CID 11899176.
- ^ a b Simard JM, Woo SK, Schwartzbauer GT, Gerzanich V (September 2012). "Sulfonylurea receptor 1 in central nervous system injury: a focused review". Journal of Cerebral Blood Flow and Metabolism. 32 (9): 1699–717. doi:10.1038/jcbfm.2012.91. PMC 3434627. PMID 22714048.
- ^ a b c Ortega FJ, Gimeno-Bayon J, Espinosa-Parrilla JF, Carrasco JL, Batlle M, Pugliese M, Mahy N, Rodríguez MJ (May 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. hdl:2445/34278. PMID 22387180. S2CID 4828181.
- ^ Simard JM, Chen M, Tarasov KV, Bhatta S, Ivanova S, Melnitchenko L, Tsymbalyuk N, West GA, Gerzanich V (April 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 JC, Junien C (2004). "Genetics of congenital hyperinsulinism". Endocrine Pathology. 15 (3): 233–40. doi:10.1385/EP:15:3:233. PMID 15640549. S2CID 24997856.
- ^ Reis AF, Velho G (February 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.