| Literature References | 1. AGUILAR-BRYAN, L., NICHOLS, C.G., WECHSLER, S.W., CLEMENT, J.P. IV,
BOYD, A.E. III, GONZALEZ, G., HERRERA-SOSA, H., NGUY, K., BRYAN, J. AND
NELSON, D.A.
Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator
of insulin secretion.
SCIENCE 268 423-426 (1995).
2. INAGAKI, N., GONOI, T., CLEMENT, J.P., IV, NAMBA, N., INAZAWA, J.,
GONZALEZ, G., AGUILAR-BRYAN, L., SEINO, S. AND BRYAN, J.
Reconstitution of IKATP: an inward rectifier plus the sulfonylurea receptor.
SCIENCE 270 1166-1170 (1995).
3. ASHCROFT, F.M. AND GRIBBLE, F.M.
Correlating structure and function in ATP-sensitive K+ channels.
TRENDS NEUROSCIENCE 21 288-294 (1998).
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| Documentation | The sulphonylurea receptor (SUR) is a member of the ATP-binding cassette
superfamily that associates with certain K+ channel inward rectifier
subunits to form ATP-sensitive K+ channels (KATP channels) [1,2]. These are
a family of K+ channels that are inhibited by intracellular ATP, which can
couple metabolic state to cell excitability. Their presence on pancreatic
islet beta cells allows the cells to function as metabolic sensors,
regulating insulin release in relation to glucose metabolism. Furthermore,
SUR is the site of action for the sulphonylurea oral hypoglycaemic agents
that are used widely for the treatment of non-insulin dependent diabetes
mellitus. When these agents bind to the sulphonlyurea receptor, they reduce
KATP channel activity, stimulating insulin release.
As mentioned, SUR is a member of the ATP-binding cassette superfamily
(traffic adenosine triphsophatase superfamily), other members including the
P-glycoprotein multi-drug resistance (MDR) proteins and the cystic
fibrosis transconductance regulators (CFTRs). This raises the possibility
that SUR may transport some endogenous substance, as yet unidentified.
Two closely related genes have been found to encode the sulphonylurea
receptors, SUR1 and SUR2, there being three splice variants of the second
form [3]. They are thought to contain 13-17 transmembrane (TM) domains,
with two potential nucleotide binding folds, and a large number of possible
protein kinase A, or C phosphorylation sites. Comparison of the properties
of cloned and wild-type KATP channels suggests that SUR1 may associate with
the inward rectifier subunit Kir6.2 to form the pancreatic beta cell KATP
channel. Splice variants of SUR2 (termed SUR2A and SUR2B) may form the
cardiac and smooth muscle isoforms, respectively, again when combined with
Kir 6.2. This co-assembly likely occurs with an obligate 4:4 stoichiometry,
giving rise to an octameric channel.
Mutations in SUR genes have been characterised; these can result in
truncations of the second predicted nucleotide binding fold, leading to
persistent hyperinsulinemic hypoglycaemia of infancy, a rare familial
disorder characterised by excessive, unregulated insulin secretion.
SULFNYLUREAR is a 5-element fingerprint that provides a signature for the
sulphonylurea receptor family. The fingerprint was derived from an initial
alignment of 13 sequences: the motifs were drawn from the N-terminal 380
residues of the molecule - motif 1 spans part of the N-terminal putative
extracellular domain and TM domain 1; motif 2 lies within the first
cytoplasmic loop; motif 3 encodes part of the second extracellular loop;
motif 4 lies at the N-terminus of the third extracellular loop; and motif
5 spans TM domain 6 and the following extracellular loop. Two iterations on
OWL31.1 were required to reach convergence, at which point a true set
comprising 17 sequences was identified.
An update on SPTR37_9f identified a true set of 15 sequences.
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