Functional Analysis of a Mutant Sulfonylurea Receptor, SUR1-R1420C, That Is Responsible for Persistent Hyperinsulinemic Hypoglycemia of Infancy

Matsuo, Masaru; Trapp, Stefan; Tanizawa, Yukio; Kioka, Noriyuki; Amachi, Teruo; Oka, Yoshitomo; Ashcroft, Frances M.; Ueda, Kazumitsu

doi:10.1074/jbc.m006503200

Cited by 42 publications

(41 citation statements)

References 39 publications

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“…The T1139M and R1215Q mutations in the ABCC8 gene cause loss of ADP-dependent gating properties of the channel and result in constitutive inhibition of K ATP channels by ATP (Dunne et al 2004). The R1420C mutation is located in SUR1-NBD2, and results of mutational studies have indicated that it reduces the affinity of NBD2 for ATP and ADP (Matsuo et al 2000). Dominant ABCC8/KCNJ11 channel mutations The identification of a single-dominant ABCC8 mutation causing CHI was identified by Huopio and colleagues.…”

Section: Channelopathiesmentioning

confidence: 99%

Molecular mechanisms of congenital hyperinsulinism

Rahman¹,

Nessa²,

Hussain³

2015

Journal of Molecular Endocrinology

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Congenital hyperinsulinism (CHI) is a complex heterogeneous condition in which insulin secretion from pancreatic b-cells is unregulated and inappropriate for the level of blood glucose. The inappropriate insulin secretion drives glucose into the insulin-sensitive tissues, such as the muscle, liver and adipose tissue, leading to severe hyperinsulinaemic hypoglycaemia (HH). At a molecular level, genetic abnormalities in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HNF4A, HNF1A, SLC16A1, UCP2 and HADH) have been identified which cause CHI. Autosomal recessive and dominant mutations in ABCC8/KCNJ11 are the commonest cause of medically unresponsive CHI. Mutations in GLUD1 and HADH lead to leucine-induced HH, and these two genes encode the key enzymes glutamate dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase which play a key role in amino acid and fatty acid regulation of insulin secretion respectively. Genetic abnormalities in HNF4A and HNF1A lead to a dual phenotype of HH in the newborn period and maturity onset-diabetes later in life. This state of the art review provides an update on the molecular basis of CHI.

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Section: Channelopathiesmentioning

confidence: 99%

Molecular mechanisms of congenital hyperinsulinism

Rahman¹,

Nessa²,

Hussain³

2015

Journal of Molecular Endocrinology

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“…Immunoblotting-Immunoblotting analyses were performed using COS-1 cells instead of COSm6 cells to reduce background (22). Transfection was carried out as described above.…”

Section: Methodsmentioning

confidence: 99%

“…The FLAG epitope tag and mutations were confirmed by DNA sequencing. All SUR1-Kir6.2 fusion constructs were also in pECE vector (22). Rat Kir6.2 cDNA is in pCDNA3 vector.…”

Section: Methodsmentioning

confidence: 99%

“…Conversely, when intracellular [ATP/ADP] ratio is low, MgADP stimulation predominates, and channel activity increases. Importantly, many PHHI-associated SUR1 mutations specifically reduce or abolish the ability of the channel to be stimulated by MgADP (13,22,23), indicating that the primary mechanism for channel activation during glucose starvation is a rise in ADP. In addition to conferring MgADP stimulation, SUR1 also mediates channel regulation by sulfonylureas and the potassium channel opener diazoxide (2,3,24).…”

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confidence: 99%

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Sulfonylureas Correct Trafficking Defects of ATP-sensitive Potassium Channels Caused by Mutations in the Sulfonylurea Receptor

Yan

Lin

Weisiger

et al. 2004

Journal of Biological Chemistry

144

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The pancreatic ATP-sensitive potassium (K ATP ) channel, a complex of four sulfonylurea receptor 1 (SUR1) and four potassium channel Kir6.2 subunits, regulates insulin secretion by linking metabolic changes to ␤-cell membrane potential. Sulfonylureas inhibit K ATP channel activities by binding to SUR1 and are widely used to treat type II diabetes. We report here that sulfonylureas also function as chemical chaperones to rescue K ATP channel trafficking defects caused by two SUR1 mutations, A116P and V187D, identified in patients with congenital hyperinsulinism. Sulfonylureas markedly increased cell surface expression of the A116P and V187D mutants by stabilizing the mutant SUR1 proteins and promoting their maturation. By contrast, diazoxide, a potassium channel opener that also binds SUR1, had no effect on surface expression of either mutant. Importantly, both mutant channels rescued to the cell surface have normal ATP, MgADP, and diazoxide sensitivities, demonstrating that SUR1 harboring either the A116P or the V187D mutation is capable of associating with Kir6.2 to form functional K ATP channels. Thus, sulfonylureas may be used to treat congenital hyperinsulinism caused by certain K ATP channel trafficking mutations. ATP-sensitive potassium (K ATP )1 channels present in the plasma membrane of pancreatic ␤-cells play a central role in mediating glucose-induced insulin secretion (1-4). The activity of K ATP channels, which regulates ␤-cell membrane potential, is determined by the relative concentrations of intracellular ATP and ADP. When the blood glucose level rises, the increased intracellular [ATP/ADP] ratio favors K ATP channel closure, resulting in membrane depolarization, Ca 2ϩ influx, and insulin secretion. When the blood glucose level falls, the above molecular events reverse, and insulin release is stopped. In the event where K ATP channels fail to open during glucose starvation, ␤-cell membrane potential remains depolarized, and insulin secretion persists, leading to severe hypoglycemia. These symptoms are found in patients suffering from congenital hyperinsulinism (5), also known as persistent hyperinsulinemia hypoglycemia of infancy (PHHI) (6). Indeed, mutations in the K ATP channel genes, sulfonylurea receptor 1 (SUR1) and the inward rectifier potassium channel Kir6.2, that lead to a loss of channel function have been shown to be major causes of PHHI (4, 6).The pancreatic K ATP channel complex consists of four poreforming Kir6.2 subunits and four regulatory SUR1 subunits (7-10). Gating of K ATP channels occurs as a result of the interplay between both channel subunits and intracellular ATP and ADP. Binding of ATP to the Kir6.2 subunit inhibits channel activity, whereas binding of Mg 2ϩ -complexed ATP or ADP to the SUR1 subunit stimulates channel activity (11)(12)(13)(14). SUR1 is a member of the ATP-binding cassette transporter family; it has three transmembrane domains: TM0, TM1, and TM2, and two large cytoplasmic nucleotide binding domains: NBD1 and NBD2 (15,16). Structure-function studies sugges...

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“…Most of the resulting K ATP channel defects can be divided into two major functional categories: (i) defects of expressed channel properties and (ii) biosynthetic or trafficking defects causing lack of, or reduced, surface expression of channels. Reduced sensitivity to channel stimulation by MgADP is a defect resulting from many HI-associated SUR1 mutations [19][20][21]. In addition, lack of, or reduced, surface expression of channels is an obvious outcome for mutations that cause large truncation of SUR1 or Kir6.2 proteins [10,22].…”

Section: Congenital Hi: Hyperexcitability and Hypersecretionmentioning

confidence: 99%

β‐cell hyperexcitability: from hyperinsulinism to diabetes

Nichols

Koster

Remedi

2007

Diabetes Obesity Metabolism

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Nutrient oxidation in b cells generates a rise in [ATP]: [ADP] ratio. This reduces K ATP channel activity, leading to depolarization, activation of voltage-dependent Ca 2þ channels, Ca 2þ entry and insulin secretion. Consistent with this paradigm, loss-of-function mutations in the genes (KCNJ11 and ABCC8) that encode the two subunits (Kir6.2 and SUR1, respectively) of the ATP-sensitive K þ (K ATP ) channel underlie hyperinsulinism in humans, a genetic disorder characterized by dysregulated insulin secretion. In mice with genetic suppression of K ATP channel subunit expression, partial loss of K ATP channel conductance also causes hypersecretion, but unexpectedly, complete loss results in an undersecreting, mildly glucose-intolerant phenotype. When challenged by a high-fat diet, normal mice and mice with reduced K ATP channel density respond with hypersecretion, but mice with more significant or complete loss of K ATP channels cross over, or progress further, to an undersecreting, diabetic phenotype. It is our contention that in mice, and perhaps in humans, there is an inverse U-shaped response to hyperexcitabilty, leading first to hypersecretion but with further exacerbation to undersecretion and diabetes. The causes of the overcompensation and diabetic susceptibility are poorly understood but may have broader implications for the progression of hyperinsulinism and type 2 diabetes in humans.

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Functional Analysis of a Mutant Sulfonylurea Receptor, SUR1-R1420C, That Is Responsible for Persistent Hyperinsulinemic Hypoglycemia of Infancy

Cited by 42 publications

References 39 publications

Molecular mechanisms of congenital hyperinsulinism

Molecular mechanisms of congenital hyperinsulinism

Sulfonylureas Correct Trafficking Defects of ATP-sensitive Potassium Channels Caused by Mutations in the Sulfonylurea Receptor

β‐cell hyperexcitability: from hyperinsulinism to diabetes

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