Sulfonylurea receptor: Difference between revisions

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In the field of [[molecular biology]], the '''sulfonylurea receptors''' ('''SUR''') are [[membrane protein]]s which are the molecular targets of the [[sulfonylurea]] class of [[antidiabetic]] drugs whose mechanism of action is to promote [[insulin]] release from [[pancreas|pancreatic]] [[beta cell]]s.  More specifically, SUR proteins are subunits of the [[inward-rectifier potassium ion channel]]s K<sub>ir</sub>6.x ([[Kir6.1|6.1]] and [[Kir6.2|6.2]]).<ref name="Campbell">{{Cite journal
In [[molecular biology]], the '''sulfonylurea receptors''' ('''SUR''') are [[membrane protein]]s which are the molecular targets of the [[sulfonylurea]] class of [[antidiabetic]] drugs whose mechanism of action is to promote [[insulin]] release from [[pancreas|pancreatic]] [[beta cell]]s.  More specifically, SUR proteins are subunits of the [[inward-rectifier potassium ion channel]]s K<sub>ir</sub>6.x ([[Kir6.1|6.1]] and [[Kir6.2|6.2]]).<ref name="Campbell">{{cite journal | vauthors = Campbell JD, Sansom MS, Ashcroft FM | title = Potassium channel regulation | journal = EMBO Reports | volume = 4 | issue = 11 | pages = 1038–42 | date = November 2003 | pmid = 14593442 | pmc = 1326373 | doi = 10.1038/sj.embor.embor7400003 | authorlink3 = Frances Ashcroft }}</ref>  The association of four K<sub>ir</sub>6.x and four SUR subunits form an ion conducting channel commonly referred to as the [[ATP-sensitive potassium channel|K<sub>ATP</sub> channel]].<ref name=mesh>{{MeshName|sulfonylurea+receptor}}</ref>
| pmid = 14593442
| pmc = 1326373
| year = 2003
| author1 = Campbell
| first1 = J. D.
| title = Potassium channel regulation
| journal = EMBO Reports
| volume = 4
| issue = 11
| pages = 1038–42
| last2 = Sansom
| first2 = M. S.
| last3 = Ashcroft
| first3 = F. M.
| authorlink3 = Frances Ashcroft
| doi = 10.1038/sj.embor.embor7400003
}}</ref>  The association of four K<sub>ir</sub>6.x and four SUR subunits form an ion conducting channel commonly referred to as the [[ATP-sensitive potassium channel|K<sub>ATP</sub> channel]].<ref name=mesh>{{MeshName|sulfonylurea+receptor}}</ref>


Three forms of the sulfonylurea receptor are known, [[ABCC8|SUR1]] encoded by the ''ABCC8'' gene, and [[ABCC9|SUR2A]] and [[ABCC9|SUR2B]], which are splice variants arising from a single ''ABCC9'' gene.<ref name="Aguilar-Bryan">{{cite journal |author=Aguilar-Bryan L, Clement JP 4th, Gonzalez G, Kunjilwar K, Babenko A, Bryan J|title=Toward understanding the assembly and structure of KATP channels|journal= Physiol Rev |volume= 78 |issue= 1 |pages= 227–45 |date=1 January 1998| url = http://physrev.physiology.org/cgi/content/abstract/78/1/227 |pmid= 9457174 }}</ref>
Three forms of the sulfonylurea receptor are known, [[ABCC8|SUR1]] encoded by the ''ABCC8'' gene, and [[ABCC9|SUR2A]] and [[ABCC9|SUR2B]], which are splice variants arising from a single ''ABCC9'' gene.<ref name="Aguilar-Bryan">{{cite journal | vauthors = Aguilar-Bryan L, Clement JP, Gonzalez G, Kunjilwar K, Babenko A, Bryan J | title = Toward understanding the assembly and structure of KATP channels | journal = Physiological Reviews | volume = 78 | issue = 1 | pages = 227–45 | date = January 1998 | pmid = 9457174 | doi = 10.1152/physrev.1998.78.1.227 | url = http://physrev.physiology.org/cgi/content/abstract/78/1/227 }}</ref>


==Function==
== Function ==
The primary function of the sulfonylurea receptor is to sense intracellular levels of the [[nucleotide]]s [[Adenosine triphosphate|ATP]] and [[Adenosine triphosphate|ADP]] and in response facilitate the open or closing its associated K<sub>ir</sub>6.x potassium channel. Hence, the K<sub>ATP</sub> channel monitors the energy balance within the cell.<ref name="Nichols">{{Cite journal | doi = 10.1038/nature04711| pmid = 16554807| title = K<sub>ATP</sub> channels as molecular sensors of cellular metabolism| journal = Nature| volume = 440| issue = 7083| pages = 470–6| year = 2006| last1 = Nichols | first1 = C. G. | authorlink1 = Colin Nichols}}</ref>
The primary function of the sulfonylurea receptor is to sense intracellular levels of the [[nucleotide]]s [[Adenosine triphosphate|ATP]] and [[Adenosine triphosphate|ADP]] and in response facilitate the open or closing its associated K<sub>ir</sub>6.x potassium channel. Hence, the K<sub>ATP</sub> channel monitors the energy balance within the cell.<ref name="Nichols">{{cite journal | vauthors = Nichols CG | title = KATP channels as molecular sensors of cellular metabolism | journal = Nature | volume = 440 | issue = 7083 | pages = 470–6 | date = March 2006 | pmid = 16554807 | doi = 10.1038/nature04711 | authorlink1 = Colin Nichols }}</ref>


Depending on the tissue in which the K<sub>ATP</sub> channel is expressed, altering the membrane potential can trigger a variety of downstream events. For example, in pancreatic [[beta cell]]s, high levels of glucose lead to increased production of ATP, which, in turn, binds to the K<sub>ATP</sub> channel resulting in channel closure. The increase in membrane potential, in turn, opens [[voltage-dependent calcium channel]]s increasing intracellular calcium concentrations, which triggers [[exocytosis]] of [[insulin]].
Depending on the tissue in which the K<sub>ATP</sub> channel is expressed, altering the membrane potential can trigger a variety of downstream events. For example, in pancreatic [[beta cell]]s, high levels of glucose lead to increased production of ATP, which, in turn, binds to the K<sub>ATP</sub> channel resulting in channel closure. The relative [[depolarization]] (decrease in membrane [[hyperpolarization (biology)| hyperpolarization]]), in turn, opens [[voltage-dependent calcium channel]]s increasing intracellular calcium concentrations, which triggers [[exocytosis]] of [[insulin]].


Under cerebral ischemic conditions, SUR1, the regulatory subunit of the K<sub>ATP-</sub> and the NC<sub>Ca-ATP</sub>-channels, is expressed in neurons, astrocytes, oligodendrocytes, endothelial cells<ref name="pmid22714048">{{cite journal |vauthors=Simard JM, Woo SK, Schwartzbauer GT, Gerzanich V |title=Sulfonylurea receptor 1 in central nervous system injury: A focused review |journal=J Cereb Blood Flow Metab |volume=32 |pages=1699–1717 |date=June 2012 |pmid=22714048 |pmc=3434627|doi=10.1038/jcbfm.2012.91 |url=http://www.nature.com/jcbfm/journal/v32/n9/full/jcbfm201291a.html |issue=9}}</ref> and by reactive microglia.<ref name="pmid22387180">{{Cite journal
Under cerebral ischemic conditions, SUR1, the regulatory subunit of the K<sub>ATP</sub> and the NC<sub>Ca-ATP</sub> channels, is expressed in neurons, astrocytes, oligodendrocytes, endothelial cells<ref name="pmid22714048">{{cite journal | vauthors = Simard JM, Woo SK, Schwartzbauer GT, Gerzanich V | title = Sulfonylurea receptor 1 in central nervous system injury: a focused review | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 32 | issue = 9 | pages = 1699–717 | date = September 2012 | pmid = 22714048 | pmc = 3434627 | doi = 10.1038/jcbfm.2012.91 | url = http://www.nature.com/jcbfm/journal/v32/n9/full/jcbfm201291a.html }}</ref> and by reactive microglia.<ref name="pmid22387180">{{cite journal | vauthors = Ortega FJ, Gimeno-Bayon J, Espinosa-Parrilla JF, Carrasco JL, Batlle M, Pugliese M, Mahy N, Rodríguez MJ | title = ATP-dependent potassium channel blockade strengthens microglial neuroprotection after hypoxia-ischemia in rats | journal = Experimental Neurology | volume = 235 | issue = 1 | pages = 282–96 | date = May 2012 | pmid = 22387180 | doi = 10.1016/j.expneurol.2012.02.010 }}</ref> Blockade of SUR1 receptors with glibenclamide has been involved in improved outcome in animal stroke models and investigational human studies by preventing brain swelling<ref name="pmid16550187">{{cite journal | vauthors = Simard JM, Chen M, Tarasov KV, Bhatta S, Ivanova S, Melnitchenko L, Tsymbalyuk N, West GA, Gerzanich V | title = Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke | journal = Nature Medicine | volume = 12 | issue = 4 | pages = 433–40 | date = April 2006 | pmid = 16550187 | pmc = 2740734 | doi = 10.1038/nm1390 }}</ref> and enhancing neuroprotection.<ref name="pmid22387180" />
| pmid = 22387180
| year = 2012
| author1 = Ortega
| first1 = F. J.
| title = ATP-dependent potassium channel blockade strengthens microglial neuroprotection after hypoxia-ischemia in rats
| journal = Experimental Neurology
| volume = 235
| issue = 1
| pages = 282–96
| last2 = Gimeno-Bayon
| first2 = J
| last3 = Espinosa-Parrilla
| first3 = J. F.
| last4 = Carrasco
| first4 = J. L.
| last5 = Batlle
| first5 = M
| last6 = Pugliese
| first6 = M
| last7 = Mahy
| first7 = N
| last8 = Rodríguez
| first8 = M. J.
| doi = 10.1016/j.expneurol.2012.02.010
}}</ref> Blockade of SUR1 receptors with glibenclamide has been involved in improved outcome in animal stroke models and investigational human studies by preventing brain swelling <ref name="pmid16550187">{{Cite journal
| pmid = 16550187
| pmc = 2740734
| year = 2006
| author1 = Simard
| first1 = J. M.
| title = Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke
| journal = Nature Medicine
| volume = 12
| issue = 4
| pages = 433–40
| last2 = Chen
| first2 = M
| last3 = Tarasov
| first3 = K. V.
| last4 = Bhatta
| first4 = S
| last5 = Ivanova
| first5 = S
| last6 = Melnitchenko
| first6 = L
| last7 = Tsymbalyuk
| first7 = N
| last8 = West
| first8 = G. A.
| last9 = Gerzanich
| first9 = V
| doi = 10.1038/nm1390
 
}}</ref> and enhancing neuroprotection.<ref name="pmid22387180" />


==Tissue distribution==
==Tissue distribution==
Line 129: Line 58:


==Disease linkage==
==Disease linkage==
The SUR1 protein is coded by the ''ABCC8'' gene and is associated with [[congenital hyperinsulinism]]<ref name="Fournet">{{Cite journal
The SUR1 protein is coded by the ''ABCC8'' gene and is associated with [[congenital hyperinsulinism]]<ref name="Fournet">{{cite journal | vauthors = Fournet JC, Junien C | title = Genetics of congenital hyperinsulinism | journal = Endocrine Pathology | volume = 15 | issue = 3 | pages = 233–40 | year = 2004 | pmid = 15640549 }}</ref> and susceptibility to [[type 2 diabetes]].<ref name="Reis">{{cite journal | vauthors = Reis AF, Velho G | title = Sulfonylurea receptor -1 (SUR1): genetic and metabolic evidences for a role in the susceptibility to type 2 diabetes mellitus | journal = Diabetes & Metabolism | volume = 28 | issue = 1 | pages = 14–9 | date = February 2002 | pmid = 11938023 }}</ref>
| pmid = 15640549
| year = 2004
| author1 = Fournet
| first1 = J. C.
| title = Genetics of congenital hyperinsulinism
| journal = Endocrine Pathology
| volume = 15
| issue = 3
| pages = 233–40
| last2 = Junien
| first2 = C
}}</ref> and susceptibility to [[type 2 diabetes]].<ref name="Reis">{{Cite journal
| pmid = 11938023
| year = 2002
| author1 = Reis
| first1 = A. F.
| title = Sulfonylurea receptor -1 (SUR1): Genetic and metabolic evidences for a role in the susceptibility to type 2 diabetes mellitus
| journal = Diabetes & metabolism
| volume = 28
| issue = 1
| pages = 14–9
| last2 = Velho
| first2 = G
}}</ref>


==References==
== References ==
{{Reflist|2}}
{{Reflist}}


{{ABC transporters}}
{{ABC transporters}}


{{gene-12-stub}}
{{gene-12-stub}}

Latest revision as of 16:19, 2 December 2018

ATP-binding cassette, subfamily C (CFTR/MRP), member 8
Identifiers
SymbolABCC8
Alt. symbolsSUR1
Entrez6833
HUGO59
OMIM600509
RefSeqNM_000352
UniProtQ09428
Other data
LocusChr. 11 p15.1
ATP-binding cassette, subfamily C (CFTR/MRP), member 9
Identifiers
SymbolABCC9
Alt. symbolsSUR2A, SUR2B
Entrez10060
HUGO60
OMIM601439
RefSeqNM_005691
UniProtO60706
Other data
LocusChr. 12 p12.1

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]

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 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

The isoforms of the sulfonylurea receptor have the following tissue distribution:

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

  1. ↑ 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.
  2. ↑ sulfonylurea+receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
  3. ↑ 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.
  4. ↑ Nichols CG (March 2006). "KATP channels as molecular sensors of cellular metabolism". Nature. 440 (7083): 470–6. doi:10.1038/nature04711. PMID 16554807.
  5. ↑ 5.0 5.1 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.
  6. ↑ 6.0 6.1 6.2 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. PMID 22387180.
  7. ↑ 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.
  8. ↑ Fournet JC, Junien C (2004). "Genetics of congenital hyperinsulinism". Endocrine Pathology. 15 (3): 233–40. PMID 15640549.
  9. ↑ 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.
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