Syntaxin-1A Binds the Nucleotide-binding Folds of Sulphonylurea Receptor 1 to Regulate the KATP Channel

Pasyk, Ewa A.; Kang, Youhou; Huang, Xiaohang; Cui, Ningren; Sheu, Laura; Gaisano, Herbert Y.

doi:10.1074/jbc.m309667200

Cited by 59 publications

(81 citation statements)

References 33 publications

(77 reference statements)

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“…The fact that the binding of Epac to SUR1 does not alter K ATP channel function favours the former possibility. However, syntaxin binding to the NBDs of SUR1 (Pasyk et al 2004) inhibits K ATP channel activity ). Another possibility is that SUR1 might be involved in granule trafficking, as we recently found that SUR1 binds a-and b-tubulin.…”

Section: Conclusion and Future Challengesmentioning

confidence: 99%

SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator

Aittoniemi

Fotinou

Craig

et al. 2008

Phil. Trans. R. Soc. B

147

132

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SUR1 is an ATP-binding cassette (ABC) transporter with a novel function. In contrast to other ABC proteins, it serves as the regulatory subunit of an ion channel. The ATP-sensitive (K ATP ) channel is an octameric complex of four pore-forming Kir6.2 subunits and four regulatory SUR1 subunits, and it links cell metabolism to electrical activity in many cell types. ATPase activity at the nucleotidebinding domains of SUR results in an increase in K ATP channel open probability. Conversely, ATP binding to Kir6.2 closes the channel. Metabolic regulation is achieved by the balance between these two opposing effects. Precisely how SUR1 talks to Kir6.2 remains unclear, but recent studies have identified some residues and domains that are involved in both physical and functional interactions between the two proteins. The importance of these interactions is exemplified by the fact that impaired regulation of Kir6.2 by SUR1 results in human disease, with loss-of-function SUR1 mutations causing congenital hyperinsulinism and gain-of-function SUR1 mutations leading to neonatal diabetes. This paper reviews recent data on the regulation of Kir6.2 by SUR1 and considers the molecular mechanisms by which SUR1 mutations produce disease.

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Section: Conclusion and Future Challengesmentioning

confidence: 99%

SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator

Aittoniemi

Fotinou

Craig

et al. 2008

Phil. Trans. R. Soc. B

147

132

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“…K ATP channel activity is also regulated by protein kinase A (PKA) in smooth muscle cells [69,70] and cytoskeletal actin in the cardiac atrium [71] . K ATP channel activity is suppressed by a SNARE protein, syntaxin 1A, via protein-protein interactions with the SUR subunits [72][73][74][75] . Syntaxin 1A decreases the activity [76] and the membrane expression level of K ATP channels [77] .…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

Sun

Feng

2012

Acta Pharmacol Sin

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ATP-sensitive potassium (K ATP ) channels are weak, inward rectifiers that couple metabolic status to cell membrane electrical activity, thus modulating many cellular functions. An increase in the ADP/ATP ratio opens K ATP channels, leading to membrane hyperpolarization. K ATP channels are ubiquitously expressed in neurons located in different regions of the brain, including the hippocampus and cortex. Brief hypoxia triggers membrane hyperpolarization in these central neurons. In vivo animal studies confirmed that knocking out the Kir6.2 subunit of the K ATP channels increases ischemic infarction, and overexpression of the Kir6.2 subunit reduces neuronal injury from ischemic insults. These findings provide the basis for a practical strategy whereby activation of endogenous K ATP channels reduces cellular damage resulting from cerebral ischemic stroke. K ATP channel modulators may prove to be clinically useful as part of a combination therapy for stroke management in the future.

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“…Our previous studies (22,23) showed that Syn-1A binds SUR1 at its NBF1 and NBF2 domains and would not bind Kir6.2. In addition, the physical interaction between SNAP-25 and SUR1 was not observed.…”

Section: Atp Dose-dependently Inhibits Syn-1a Binding To Sur1-mentioning

confidence: 99%

“…In Vitro Binding Assay and Western Blotting-In vitro binding assays were performed according to the methods we described previously (22). Briefly, GST (as a negative control) and GST-Syn-1A (350 pmol protein each) were bound to glutathione-agarose beads and incubated with 0.5 ml SUR1 overexpressing HEK293 cell lysate extract (400 g protein in lysis buffer containing 20 mM HEPES (pH 7.4), 100 mM KCl, 1.5% Triton X-100, 1 g/ml pepstatin A, 1 g/ml leupeptin, and 10 g/ml aprotinin) in the presence or absence of different concentrations of ATP (Sigma) along with or without 2 mM MgCl 2 at 4°C for 2 h with constant agitation, followed by washing the beads three times with washing buffer containing 20 mM HEPES (pH 7.4), 150 mM KOAC, 1 mM EDTA, 5% glycerol, and 0.1% Triton X-100.…”

Section: Constructs and Recombinant Gst-fusion Proteins-pgex-mentioning

confidence: 99%

“…Remarkably, we have reported that pancreatic ␤-cell K ATP channels can also be regulated by endogenous plasma membrane-bound syntaxin-1A (Syn-1A), a SNARE protein originally described to mediate exocytic membrane fusion. In contrast to the cytosolic factors that act on the Kir6.2 subunit (18 -20), Syn-1A binds the SUR subunits at both NBFs to regulate K ATP channel gating (21,22).…”

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ATP Modulates Interaction of Syntaxin-1A with Sulfonylurea Receptor 1 to Regulate Pancreatic β-Cell KATP Channels

Kang

Zhang

Liang

et al. 2011

Journal of Biological Chemistry

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ATP-sensitive potassium (K ATP ) channels are regulated by a variety of cytosolic factors (adenine nucleotides, Mg2؉ , phospholipids, and pH). We previously reported that K ATP channels are also regulated by endogenous membrane-bound SNARE protein syntaxin-1A (Syn-1A), which binds both nucleotide-binding folds of sulfonylurea receptor (SUR)1 and 2A, causing inhibition of K ATP channel activity in pancreatic islet ␤-cells and cardiac myocytes, respectively. In this study, we show that ATP dose-dependently inhibits Syn-1A binding to SUR1 at physiological concentrations, with the addition of Mg 2؉ causing a decrease in the ATP-induced inhibitory effect. This ATP disruption of Syn-1A binding to SUR1 was confirmed by FRET analysis in living HEK293 cells. Electrophysiological studies in pancreatic ␤-cells demonstrated that reduced ATP concentrations increased K ATP channel sensitivity to Syn-1A inhibition. Depletion of endogenous Syn-1A in insulinoma cells by botulinum neurotoxin C1 proteolysis followed by rescue with exogenous Syn-1A showed that Syn-1A modulates K ATP channel sensitivity to ATP. Thus, our data indicate that although both ATP and Syn-1A independently inhibit ␤-cell K ATP channel gating, they could also influence the sensitivity of K ATP channels to each other. These findings provide new insight into an alternate mechanism by which ATP regulates pancreatic ␤-cell K ATP channel activity, not only by its direct actions on Kir6.2 pore subunit, but also via ATP modulation of Syn-1A binding to SUR1.The ATP-sensitive potassium (K ATP ) 3 channel couples intracellular metabolic changes to plasma membrane electrical activity in many cell types (1-3). In pancreatic ␤-cells, increase in ATP/ADP ratio from glucose metabolism closes plasma membrane K ATP channels, causing membrane depolarization that leads to opening of L-type voltage-dependent calcium channels. Ensuing calcium influx triggers exocytosis of docked and primed insulin granules in part by acting on the exocytic SNARE (soluble NSF attachment protein receptor) complex (4). The pancreatic ␤-cell K ATP channel is a heterooctamer of pore-forming Kir 6.2 and regulatory sulfonylurea receptor 1 (SUR1) subunits, with a 4:4 stoichiometry (5-7). SURs are members of the ATP-binding cassette protein superfamily (8), including cystic fibrosis transmembrane conductance regulator and P-glycoprotein/MDR1 (multidrug resistance 1). These ATP-binding cassette proteins uniformly contain two nucleotide-binding folds (NBF1 and NBF2), with each NBF containing Walker A and B motifs, which are sites of the action by adenine nucleotides. Regulation of K ATP channels by adenine nucleotides is complex, with ATP and ADP having both stimulatory and inhibitory effects (9 -11). Structure-function studies have demonstrated that ATP inhibits channel activity by interactions with Kir6.2 (12), whereas ADP acts on the SUR subunit to stimulate channel activity in an Mg 2ϩ -dependent manner (13). The importance of SUR1 as a regulator of K ATP channel activity is demonstrated by the fact th...

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Syntaxin-1A Binds the Nucleotide-binding Folds of Sulphonylurea Receptor 1 to Regulate the KATP Channel

Cited by 59 publications

References 33 publications

SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator

SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator

Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

ATP Modulates Interaction of Syntaxin-1A with Sulfonylurea Receptor 1 to Regulate Pancreatic β-Cell KATP Channels

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