Abnormal KCNQ1 trafficking influences disease pathogenesis in hereditary long QT syndromes (LQT1)

Wilson, Andrew J.; Quinn, K.; Graves, Fiona M.; Bitner‐Glindzicz, Maria; Tinker, Andrew

doi:10.1016/j.cardiores.2005.04.036

Cited by 69 publications

(75 citation statements)

References 51 publications

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“…10). Recent evidence demonstrates that the normal trafficking to the plasma membrane of KCNQ1 is disrupted in channels bearing mutations associated with disease in nonhepatic tissue (47). The molecular identification of KCNQ1/KCNE3 in rat and human liver (27) and characterization of the signaling pathways involved in I KVol activation reported should permit discovery of ways in which to manipulate channel activity and ameliorate specific liver dysfunctions.…”

Section: Discussionmentioning

confidence: 99%

Modulation of hepatocellular swelling-activated K⁺ currents by phosphoinositide pathway-dependent protein kinase C

Wang¹,

Hill²

2006

American Journal of Physiology-Cell Physiology

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K+ channels participate in the regulatory volume decrease (RVD) accompanying hepatocellular nutrient uptake and bile formation. We recently identified KCNQ1 as a molecular candidate for a significant fraction of the hepatocellular swelling-activated K+ current ( IKVol). We have shown that the KCNQ1 inhibitor chromanol 293B significantly inhibited RVD-associated K+ flux in isolated perfused rat liver and used patch-clamp techniques to define the signaling pathway linking swelling to IKVol activation. Patch-electrode dialysis of hepatocytes with solutions that maintain or increase phosphatidylinositol 4,5-bisphosphate (PIP2) increased IKVol, whereas conditions that decrease cellular PIP2 decreased IKVol. GTP and AlF4− stimulated IKVol development, suggesting a role for G proteins and phospholipase C (PLC). Supporting this, the PLC blocker U-73122 decreased IKVol and inhibited the stimulatory response to PIP2 or GTP. Protein kinase C (PKC) is involved, because K+ current was enhanced by 1-oleoyl-2-acetyl- sn-glycerol and inhibited after chronic PKC stimulation with phorbol 12-myristate 13-acetate (PMA) or the PKC inhibitor GF 109203X. Both IKVol and the accompanying membrane capacitance increase were blocked by cytochalasin D or GF 109203X. Acute PMA did not eliminate the cytochalasin D inhibition, suggesting that PKC-mediated IKVol activation involves the cytoskeleton. Under isotonic conditions, a slowly developing K+ current similar to IKVol was activated by PIP2, lipid phosphatase inhibitors to counter PIP2 depletion, a PLC-coupled α1-adrenoceptor agonist, or PKC activators and was depressed by PKC inhibition, suggesting that hypotonicity is one of a set of stimuli that can activate IKVol through a PIP2/PKC-dependent pathway. The results indicate that PIP2 indirectly activates hepatocellular KCNQ1-like channels via cytoskeletal rearrangement involving PKC activation.

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Section: Discussionmentioning

confidence: 99%

Modulation of hepatocellular swelling-activated K⁺ currents by phosphoinositide pathway-dependent protein kinase C

Wang¹,

Hill²

2006

American Journal of Physiology-Cell Physiology

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“…Pipette resistance, when filled with intracellular solution, was ϳ1.5-2.5 megaohms, and pipette capacitance was reduced by coating the tip with a parafilm oil suspension. Data were analyzed using Clampfit and Microcal Origin software (23,31). Current-voltage relationships were determined by normalizing the maximal current densities at the end of each pulse potential to cell capacitance (nA or pA/pF).…”

Section: Methodsmentioning

confidence: 99%

“…We introduced these alanine mutations singly or in combination into KCNQ1-GFP and co-expressed them with KCNE1 in CHO-K1 cells to replicate the molecular basis of the cardiac current. We have previously shown that KCNQ1-GFP behaves in an essentially identical fashion to KCNQ1 from a functional point of view (31). We used whole cell patching to measure and characterize the currents.…”

Section: What Are the Effects Of These Mutations On Channelmentioning

confidence: 99%

Characterization of a Binding Site for Anionic Phospholipids on KCNQ1

Thomas¹,

Harmer²,

Khambra

et al. 2011

Journal of Biological Chemistry

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The KCNQ family of potassium channels underlie a repolarizing K ؉ current in the heart and the M-current in neurones.The assembly of KCNQ1 with KCNE1 generates the delayed rectifier current I Ks in the heart. Characteristically these channels are regulated via G q/11 -coupled receptors and the inhibition seen after phospholipase C activation is now thought to occur from membrane phosphatidylinositol (4,5)-bisphosphate (PIP 2 ) depletion. It is not clear how KCNQ1 recognizes PIP 2 and specifically which residues in the channel complex are important. Using biochemical techniques we identify a cluster of basic residues namely, Lys-354, Lys-358, Arg-360, and Lys-362, in the proximal C terminus as being involved in binding anionic phospholipids. The mutation of specific residues in combination, to alanine leads to the loss of binding to phosphoinositides. Functionally, the introduction of these mutations into KCNQ1 leads to shifts in the voltage dependence of channel activation toward depolarized potentials and reductions in current density. Additionally, the biophysical effects of the charge neutralizing mutations, which disrupt phosphoinositide binding, mirror the effects we see on channel function when we deplete cellular PIP 2 levels through activation of a G q/11 -coupled receptor. Conversely, the addition of diC8-PIP 2 to the wild-type channel, but not a PIP 2 binding-deficient mutant, acts to shift the voltage dependence of channel activation toward hyperpolarized potentials and increase current density.In conclusion, we use a combined biochemical and functional approach to identify a cluster of basic residues important for the binding and action of anionic phospholipids on the KCNQ1/KCNE1 complex.

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“…Several other cardiac ion channel subunit mutations cause impaired trafficking and have been linked with proarrhythmic syndromes including KCNQ1 (long QT1), 9 the majority of studied KCNH2 mutations (long QT2), 10 the potassium channel KCNJ2 (Andersen-Tawil), 11 SCN5A (CCD and Brugada syndrome), 12 and the hyperpolarization-activated cyclic nucleotide-gated channel 4 gene (sinus node disease). 13 In all of these examples, mutations result in trafficking-deficient proteins that fail to reach the plasma membrane, causing a loss of function.…”

Section: Article See P 374mentioning

confidence: 99%

Trpm4-Linked Isolated Cardiac Conduction Defects

Mills

Milan

2010

Circ Cardiovasc Genet

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Abnormal KCNQ1 trafficking influences disease pathogenesis in hereditary long QT syndromes (LQT1)

Abstract: Our data revealed that channel trafficking may contribute to the pathogenesis of LQT1.

Cited by 69 publications

References 51 publications

Modulation of hepatocellular swelling-activated K⁺ currents by phosphoinositide pathway-dependent protein kinase C

Modulation of hepatocellular swelling-activated K⁺ currents by phosphoinositide pathway-dependent protein kinase C

Characterization of a Binding Site for Anionic Phospholipids on KCNQ1

Trpm4-Linked Isolated Cardiac Conduction Defects

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Abnormal KCNQ1 trafficking influences disease pathogenesis in hereditary long QT syndromes (LQT1)

Abstract: Our data revealed that channel trafficking may contribute to the pathogenesis of LQT1.

Cited by 69 publications

References 51 publications

Modulation of hepatocellular swelling-activated K+ currents by phosphoinositide pathway-dependent protein kinase C

Modulation of hepatocellular swelling-activated K+ currents by phosphoinositide pathway-dependent protein kinase C

Characterization of a Binding Site for Anionic Phospholipids on KCNQ1

Trpm4-Linked Isolated Cardiac Conduction Defects

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Product

Resources

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Modulation of hepatocellular swelling-activated K⁺ currents by phosphoinositide pathway-dependent protein kinase C

Modulation of hepatocellular swelling-activated K⁺ currents by phosphoinositide pathway-dependent protein kinase C