Structurally Distinct Ligands Rescue Biogenesis Defects of the KATP Channel Complex via a Converging Mechanism

Devaraneni, Prasanna K.; Martin, Gregory M.; Olson, Edwin S.; Zhou, Qing; Show-Ling, Shyng,

doi:10.1074/jbc.m114.634576

Cited by 35 publications

(67 citation statements)

References 69 publications

(55 reference statements)

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“…The catalytic subdomain contains Walker A and B conserved motifs that play important roles in ATP binding and hydrolysis. The A motif (P-loop) contains a highly conserved lysine residue that interacts with the b and g phosphates of the nucleotides (Devaraneni et al, 2015 residue that binds the g-phosphate of ATP through a water molecule (Beis, 2015). Downstream the Walker B motif, the catalytic base consists on a glutamate residue that both hydrolyzes ATP and forms a dyad with the H-loop histidine of the antiparallel NBD (Jones and George, 2012).…”

Section: Molecular Structure Of K Atp Channel and Sur1 Nucleotide Binmentioning

confidence: 99%

“…There are three isoforms of the sulfonylurea receptor: SUR1, SUR2A, and SUR2B (Devaraneni et al, 2015). The sulfonylurea receptor is a regulatory subunit because it: 1) confers sensitivity to Mg-nucleotides, 2) is activated by K 1 channel openers such as diazoxide and pinacidil, and 3) is inhibited by sulfonylureas such as glibenclamide and tolbutamide (Aguilar-Bryan and Bryan, 1999).…”

Section: Molecular Structure Of K Atp Channel and Sur1 Nucleotide Binmentioning

confidence: 99%

“…Moreover, the N-terminal domain (TMD0) has five transmembrane helices connected to the TMD1 through a long cytosolic loop known as the L0 or CL3 linker ( Fig. 1) (Devaraneni et al, 2015).…”

Section: Molecular Structure Of K Atp Channel and Sur1 Nucleotide Binmentioning

confidence: 99%

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Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

et al. 2016

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Pancreatic beta cells, unique cells that secrete insulin in response to an increase in glucose levels, play a significant role in glucose homeostasis. Glucose-stimulated insulin secretion (GSIS) in pancreatic beta cells has been extensively explored. In this mechanism, glucose enters the cells and subsequently the metabolic cycle. During this process, the ATP/ADP ratio increases, leading to ATP-sensitive potassium (K ATP ) channel closure, which initiates depolarization that is also dependent on the activity of TRP nonselective ion channels. Depolarization leads to the opening of voltage-gated Na 1 channels (Nav) and subsequently voltage-dependent Ca 21 channels (Cav).The increase in intracellular Ca 21 triggers the exocytosis of insulin-containing vesicles. Thus, electrical activity of pancreatic beta cells plays a central role in GSIS. Moreover, many growth factors, incretins, neurotransmitters, and hormones can modulate GSIS, and the channels that participate in GSIS are highly regulated. In this review, we focus on the principal ionic channels (K ATP , Nav, and Cav channels) involved in GSIS and how classic and new proteins, hormones, and drugs regulate it. Moreover, we also discuss advances on how metabolic disorders such as metabolic syndrome and diabetes mellitus change channel activity leading to changes in insulin secretion.

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Section: Molecular Structure Of K Atp Channel and Sur1 Nucleotide Binmentioning

confidence: 99%

Section: Molecular Structure Of K Atp Channel and Sur1 Nucleotide Binmentioning

confidence: 99%

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Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

et al. 2016

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“…COSm6 cells co-transfected with mutant SUR1 and WT Kir6.2 cDNAs (both human forms of the gene) were treated overnight (ϳ16 h) with vehicle control (0.1% DMSO), 5 M GBC, or 10 M CBZ followed by Western blotting of the wholecell lysate. GBC was included as a comparison, because this sulfonylurea has been shown to be the most effective pharmacological chaperone for multiple TMD0 trafficking mutations (13,15) and acts similarly to CBZ (23). WT SUR1/Kir6.2 was also included in each blot to serve as a positive control.…”

Section: Identification and Pharmacological Rescue Of Novel Hi-causinmentioning

confidence: 99%

“…Remarkably, the SUR1 trafficking mutations tested so far that are amenable to rescue by SUs or CBZ are all in TMD0 (13,15,17,19), a region known to mediate functional and physical interactions between SUR1 and Kir6.2 (20 -22). Accordingly, we have found that the rescue effect of GBC and CBZ on TMD0 mutants is dependent on Kir6.2 and that both drugs promote the interaction between Kir6.2 and SUR1 (13,23), suggesting that the pharmacological chaperones work in concert with Kir6.2 during translation and/or folding to overcome the structural defects imposed by the TMD0-SUR1 mutations. Importantly, mutants rescued to the cell surface by the reversible inhibitor CBZ or the reversible sulfonylurea tolbutamide often retain normal responses to ATP and MgADP upon drug washout (13,15,17), suggesting that these mutant channels may reestablish normal insulin secretion if surface expression is restored.…”

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confidence: 99%

Pharmacological Correction of Trafficking Defects in ATP-sensitive Potassium Channels Caused by Sulfonylurea Receptor 1 Mutations

Martin

Rex

Devaraneni

et al. 2016

Journal of Biological Chemistry

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ATP-sensitive potassium (K ATP ) channels play a key role in mediating glucose-stimulated insulin secretion by coupling metabolic signals to ␤-cell membrane potential. Loss of K ATP channel function due to mutations in ABCC8 or KCNJ11, genes encoding the sulfonylurea receptor 1 (SUR1) or the inwardly rectifying potassium channel Kir6.2, respectively, results in congenital hyperinsulinism. Many SUR1 mutations prevent trafficking of channel proteins from the endoplasmic reticulum to the cell surface. Channel inhibitors, including sulfonylureas and carbamazepine, have been shown to correct channel trafficking defects. In the present study, we identified 13 novel SUR1 mutations that cause channel trafficking defects, the majority of which are amenable to pharmacological rescue by glibenclamide and carbamazepine. By contrast, none of the mutant channels were rescued by K ATP channel openers. Cross-linking experiments showed that K ATP channel inhibitors promoted interactions between the N terminus of Kir6.2 and SUR1, whereas channel openers did not, suggesting the inhibitors enhance intersubunit interactions to overcome channel biogenesis and trafficking defects. Functional studies of rescued mutant channels indicate that most mutants rescued to the cell surface exhibited WT-like sensitivity to ATP, MgADP, and diazoxide. In intact cells, recovery of channel function upon trafficking rescue by reversible sulfonylureas or carbamazepine was facilitated by the K ATP channel opener diazoxide. Our study expands the list of K ATP channel trafficking mutations whose function can be recovered by pharmacological ligands and provides further insight into the structural mechanism by which channel inhibitors correct channel biogenesis and trafficking defects.Protein function relies on the proper folding, assembly, and trafficking to specific cellular compartments. In the case of plasma membrane proteins, such as ion channels and receptors, they must pass quality surveillance in the endoplasmic reticulum (ER) 3 to enter the secretory pathway and ultimately reach the cell surface. Numerous diseases arise due to mutations that disrupt protein folding, assembly, and subsequent trafficking to the cell surface (1), hereafter referred to as trafficking mutations. Small molecules termed pharmacological chaperones hold promise as a means of therapy for such diseases by interacting with mutant proteins and correcting their folding and trafficking defects (2-4).Congenital hyperinsulinism (HI) is a rare, life-threatening disease characterized by persistent insulin secretion despite extreme hypoglycemia (5). The most common cause of HI is loss-of-function mutations in the ABCC8 or KCNJ11 genes encoding the sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel Kir6.2 proteins, respectively (5-7). SUR1 and Kir6.2 form the pancreatic subtype of the ATP-sensitive K ϩ (K ATP ) channel, which plays a key role in glucosestimulated insulin secretion by coupling glucose metabolism to ␤-cell membrane excitability (7-9). SUR1 or Kir...

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Pharmacological Chaperones: Beyond Conformational Disorders

Leidenheimer

2017

Targeting Trafficking in Drug Development

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Pharmacological chaperones (PCs) are small molecules that bind to nascent protein targets to facilitate their biogenesis. The ability of PCs to assist in the folding and subsequent forward trafficking of disease-causative protein misfolding mutants has opened new avenues for the treatment of conformational diseases such as cystic fibrosis and lysosomal storage disorders. In this chapter, an overview of the use of PCs for the treatment of conformational disorders is provided. Beyond the therapeutic application of PCs for the treatment of these disorders, pharmacological chaperoning of wild-type integral membrane proteins is discussed. Central to this discussion is the notion that the endoplasmic reticulum is a reservoir of viable but inefficiently processed wild-type protein folding intermediates whose biogenesis can be facilitated by PCs to increase functional pools. To date, the potential therapeutic use of PCs to enhance the biogenesis of wild-type proteins has received little attention. Here the rationale for the development of PCs that target WT proteins is discussed. Also considered is the likelihood that some commonly used therapeutic agents may exert unrecognized pharmacological chaperoning activity on wild-type targets in patient populations.

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Structurally Distinct Ligands Rescue Biogenesis Defects of the KATP Channel Complex via a Converging Mechanism

Cited by 35 publications

References 69 publications

Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

Pharmacological Correction of Trafficking Defects in ATP-sensitive Potassium Channels Caused by Sulfonylurea Receptor 1 Mutations

Pharmacological Chaperones: Beyond Conformational Disorders

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