Coronary spasm and acute myocardial infarction due to a mutation (V734I) in the nucleotide binding domain 1 of ABCC9

Smith, Keith; Chadburn, Andrew J.; Adomaviciene, Aiste; Minoretti, Piercarlo; Vignali, Luigi; Emanuele, Enzo; Tammaro, Paolo

doi:10.1016/j.ijcard.2013.04.210

Cited by 31 publications

(24 citation statements)

References 62 publications

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“…Site‐directed mutagenesis was performed as described previously (Tammaro and Ashcroft, ). HEK‐293T cells were cultured as previously described (Smith et al, ) and transfected with 0.6 μg of TMEM16A or TMEM16B, 1 μg of DrVSP or PIPK and 0.2 μg of CD8 constructs using Fugene HD (Promega, UK) according to the manufacturer's instructions. Cells were used ~12–36 h after transfection.…”

Section: Methodsmentioning

confidence: 99%

Contrasting effects of phosphatidylinositol 4,5‐bisphosphate on cloned TMEM16A and TMEM16B channels

Acheson

Rorsman

et al. 2017

British J Pharmacology

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Ca2+ -activated Cl À channels (CaCCs) are gated open by a rise in intracellular Ca 2+ concentration ([Ca 2+ ] i ), typically provoked by activation of G q -protein coupled receptors (G q PCR). G q PCR activation initiates depletion of plasmalemmal phosphatidylinositol 4,5-bisphosphate (PIP 2 ). Here, we determined whether PIP 2 acts as a signalling lipid for CaCCs coded by the TMEM16A and TMEM16B genes. EXPERIMENTAL APPROACHPatch-clamp electrophysiology, in conjunction with genetically encoded systems to control cellular PIP 2 content, was used to define the mechanism of action of PIP 2 on TMEM16A and TMEM16B channels. KEY RESULTSA water-soluble PIP 2 analogue (diC8-PIP 2 ) activated TMEM16A channels by up to fivefold and inhibited TMEM16B by~0.2-fold. The effects of diC8-PIP 2 on TMEM16A currents were especially pronounced at low [Ca 2+ ] i . In contrast, diC8-PIP 2 modulation of TMEM16B channels did not vary over a broad [Ca 2+ ] i range but was only detectable at highly depolarized membrane potentials. Modulation of TMEM16A and TMEM16B currents was due to changes in channel gating, while single channel conductance was unaltered. Co-expression of TMEM16A or TMEM16B with a Danio rerio voltage-sensitive phosphatase (DrVSP), which degrades PIP 2 , led to reduction and enhancement of TMEM16A and TMEM16B currents respectively. These effects were abolished by an inactivating mutation in DrVSP and antagonized by simultaneous co-expression of a phosphatidylinositol-4-phosphate 5-kinase that catalyses PIP 2 formation. CONCLUSIONS AND IMPLICATIONSPIP 2 acts as a modifier of TMEM16A and TMEM16B channel gating. Drugs interacting with PIP 2 signalling may affect TMEM16A and TMEM16B channel gating and have potential uses in basic science and implications for therapy. AbbreviationsCaCC, calcium-activated chloride channel; DrVSP, Danio rerio voltage-sensitive phosphatase; E rev , reversal potential; G q PCR, G q -protein coupled receptors; IP 3 , inositol triphosphate; PIP 2 , phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; PIPK, PIP 5-kinase type Iγ; V m , membrane potential

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Section: Methodsmentioning

confidence: 99%

Contrasting effects of phosphatidylinositol 4,5‐bisphosphate on cloned TMEM16A and TMEM16B channels

Acheson

Rorsman

et al. 2017

British J Pharmacology

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“…Whereas Cantu syncrome is a congenital defect that may have pleitropic manifestations, a number of exonic ABCC9 variants have been associated with cardiovascular diseases including atrial fibrillation, vasospasm, dilated cardiomyopathy, and myocardial infarction (Barajas-Martinez, et al, 2012,Beziau, et al, 2014,Bienengraeber, et al, 2004,Kane, et al, 2005,Nichols, et al, 2013,Olson, et al, 2007,Smith, et al, 2013); Table 2. Variants in ABCC9 have also been reported in association with Brugada (cardiovascular) syndrome and early repolarization syndrome (Barajas-Martinez, et al, 2012,Hu, et al, 2014).…”

Section: Abcc9 Gene Variants In Human Diseases: Overviewmentioning

confidence: 99%

ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target

Nelson

Jicha

Wang

et al. 2015

Ageing Research Reviews

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The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium (“KATP”) channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The KATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is a result of ABCC9 mutations; we discuss neurologic manifestations of this genetic syndrome. More common brain disorders linked to ABCC9 gene variants include hippocampal sclerosis of aging (HS-Aging), sleep disorders, and depression. HS-Aging is a prevalent neurological disease with pathologic features of both neurodegenerative (aberrant TDP-43) and cerebrovascular (arteriolosclerosis) disease. As to potential therapeutic intervention, the human pharmacopeia features both SUR2 agonists and antagonists, so ABCC9/SUR2 may provide a “druggable target”, relevant perhaps to both HS-Aging and Alzheimer’s disease. We conclude that more work is required to better understand the roles of ABCC9/SUR2 in the human brain during health and disease conditions.

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“…Interestingly, a recent study reported that V734I reduced the sensitivity of Kir6.2/SUR2B channels but not of Kir6.2/SUR2A or Kir6.1/SUR2B channels, to MgATP inhibition[37]. The methodology employed was similar to that used in our study in which the mutant produced a significant gain of function of I K-ATP .…”

Section: Discussionmentioning

confidence: 89%

ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene

Barajas-Martínez

Terzic

et al. 2014

International Journal of Cardiology

114

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Background Genetic defects in KCNJ8, encoding the Kir6.1 subunit of the ATP-sensitive K+ channel (IK-ATP), have previously been associated with early repolarization (ERS) and Brugada (BrS) syndromes. Here we test the hypothesis genetic variants in ABCC9, encoding the ATP-binding cassette transporter of IK-ATP (SUR2A), are also associated with both BrS and ERS. Methods and Results Direct sequencing of all ERS/BrS susceptibility genes was performed on 150 probands and family members. Whole-cell and inside-out patch-clamp methods were used to characterize mutant channels expressed in TSA201-cells. Eight ABCC9 mutations were uncovered in 11 male BrS probands. Four probands, diagnosed with ERS, carried a highly-conserved mutation, V734I-ABCC9. Functional expression of the V734I variant yielded a Mg-ATP IC50 that was 5-fold that of wild-type (WT). An 18-y/o male with global ERS, inherited an SCN5A-E1784K mutation from his mother, who displayed long QT intervals, and S1402C-ABCC9 mutation from his father, who displayed an ER pattern. ABCC9-S1402C likewise caused a gain of function of IK-ATP with a shift of ATP IC50 from 8.5±2 mM to 13.4±5 μM (p<0.05). The SCN5A mutation reduced peak INa to 39% of WT (p<0.01), shifted steady-state inactivation by −18.0mV (p<0.01) and increased late INa from 0.14% to 2.01% of peak INa (p<0.01). Conclusion Our study is the first to identify ABCC9 as a susceptibility gene for ERS and BrS. Our findings also suggest that a gain-of-function in IK-ATP when coupled with a loss-of-function in SCN5A may underlie type 3 ERS, which is associated with a severe arrhythmic phenotype.

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Coronary spasm and acute myocardial infarction due to a mutation (V734I) in the nucleotide binding domain 1 of ABCC9

Cited by 31 publications

References 62 publications

Contrasting effects of phosphatidylinositol 4,5‐bisphosphate on cloned TMEM16A and TMEM16B channels

Contrasting effects of phosphatidylinositol 4,5‐bisphosphate on cloned TMEM16A and TMEM16B channels

ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target

ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene

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