KvLQT1 and IsK (minK) proteins associate to form the IKS cardiac potassium current

Barhanin, Jacques; Lesage, Florian; Guillemare, Eric; Fink, Michel; Lazdunski, Michel; Romey, Georges

doi:10.1038/384078a0

Cited by 1,514 publications

(1,297 citation statements)

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“…The first identified, KCNQ1, localizes to the heart, where it associates with the minK (IsK) subunit to produce the cardiac current called I K s (Barhanin et al, 1996;Sanguinetti et al, 1996). Mutations in KCNQ1 cause a form of long-QT syndrome of cardiac arrythmias and deafness (Barhanin et al, 1996;Sanguinetti et al, 1996;Neyroud et al, 1997). KCNQ2 and KCNQ3 are not expressed in the heart but rather in numerous brain regions and sympathetic ganglia (Biervert et al, 1998;Wang et al, 1998;Yang et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…The importance of each member is reflected in human genetic disorders attributed to them. The first identified, KCNQ1, localizes to the heart, where it associates with the minK (IsK) subunit to produce the cardiac current called I K s (Barhanin et al, 1996;Sanguinetti et al, 1996). Mutations in KCNQ1 cause a form of long-QT syndrome of cardiac arrythmias and deafness (Barhanin et al, 1996;Sanguinetti et al, 1996;Neyroud et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

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Reconstitution of Muscarinic Modulation of the KCNQ2/KCNQ3 K⁺Channels That Underlie the Neuronal M Current

Shapiro¹,

Roche²,

Kaftan³

et al. 2000

J. Neurosci.

194

243

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Channels from KCNQ2 and KCNQ3 genes have been suggested to underlie the neuronal M-type K ϩ current. The M current is modulated by muscarinic agonists via G-proteins and an unidentified diffusible cytoplasmic messenger. Using wholecell clamp, we studied tsA-201 cells in which cloned KCNQ2/ KCNQ3 channels were coexpressed with M 1 muscarinic receptors. Heteromeric KCNQ2/KCNQ3 currents were modulated by the muscarinic agonist oxotremorine-M (oxo-M) in a manner having all of the characteristics of modulation of native M current in sympathetic neurons. Oxo-M also produced obvious intracellular Ca 2ϩ transients, observed by using indo-1 fluorescence. However, modulation of the current remained strong even when Ca 2ϩ signals were abolished by the combined use of strong intracellular Ca 2ϩ buffers, an inhibitor of IP 3 receptors, and thapsigargin to deplete Ca 2ϩ stores. Muscarinic modulation was not blocked by staurosporine, a broad-spectrum protein kinase inhibitor, arguing against involvement of protein kinases. The modulation was not associated with a shift in the voltage dependence of channel activation. Homomeric KCNQ2 and KCNQ3 channels also expressed well and were modulated individually by oxo-M, suggesting that the motifs for modulation are present on both channel subtypes. Homomeric KCNQ2 and KCNQ3 currents were blocked, respectively, at very low and at high concentrations of tetraethylammonium ion. Finally, when KCNQ2 subunits were overexpressed by intranuclear DNA injection in sympathetic neurons, total M current was fully modulated by the endogenous neuronal muscarinic signaling mechanism. Our data further rule out Ca 2ϩ as the diffusible messenger. The reconstitution of muscarinic modulation of the M current that uses cloned components should facilitate the elucidation of the muscarinic signaling mechanism. Key words: K ϩ channel; muscarinic receptor; G-protein; calcium; patch clamp; M current A diverse family of neurotransmitters and hormones regulates Ca 2ϩ and K ϩ channels via G-protein-mediated signaling pathways (Wickman and Clapham, 1995;Brown et al., 1997;Dolphin, 1998). Nearly 20 years ago, several investigators gave the name M current to a noninactivating K ϩ current with slow kinetics in sympathetic neurons that is strongly suppressed by muscarinic acetylcholine receptor (mAChR) agonists (Brown and Adams, 1980;Constanti and Brown, 1981). The M current is thought to play an important role in neuronal excitability, and its suppression increases responses to excitatory synaptic inputs (Jones et al., 1995;Wang and McKinnon, 1995). Modulation of the M current by muscarinic receptor agonists and by angiotensin (Constanti and Brown, 1981; Marrion, 1997;Shapiro et al., 1994a) is mediated by a G-protein of the G q /11 class (Delmas et al., 1998; Haley et al., 1998) via a diffusible cytoplasmic second messenger (Selyanko et al., 1992) that is yet to be identified.Although the buffering of intracellular free Ca 2ϩ ([Ca 2ϩ ] i ) to very low levels prevents muscarinic suppression of the M current in rat sym...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Reconstitution of Muscarinic Modulation of the KCNQ2/KCNQ3 K⁺Channels That Underlie the Neuronal M Current

Shapiro¹,

Roche²,

Kaftan³

et al. 2000

J. Neurosci.

194

243

View full text Add to dashboard Cite

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“…For example, the inhibitor E-4031 leads to significant perturbation of the SAN action potential and dofetilide (another blocker) slows pacemaking [61]. In contrast, I Ks is characteristically activates slowly and the channel complex is formed by KCNQ1 (Kv7.1) and the β subunit KCNE1 [67,68]. There may be some species differences in the relative magnitudes of I Kr and I Ks but I Ks is also clearly present in the SAN [69,70].…”

Section: Repolarising Currentsmentioning

confidence: 99%

Potassium channels in the sinoatrial node and their role in heart rate control

Aziz

Tinker

2018

Channels

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Potassium currents determine the resting membrane potential and govern repolarisation in cardiac myocytes. Here, we review the various currents in the sinoatrial node focussing on their molecular and cellular properties and their role in pacemaking and heart rate control. We also describe how our recent finding of a novel ATP-sensitive potassium channel population in these cells fits into this picture.

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“…Loss of function mutation in KCNQ1 and KCNE1 genes, which encode the α and β subunits of the slowly activating delayed rectifier potassium current (I Ks ), are responsible for subtypes of LQTS known as LQT1 and LQT5, respectively (Barhanin et al, 1996;Sanguinetti et al, 1996). Similarly, loss of function mutations in KCNH2 and KCNE2 genes which encode the α and β (MiRP1) subunit of the rapidly activating delayed rectifier potassium current (I Kr ) is responsible for LQT2 and LQT6 subtypes (Sanguinetti et al, 1995;Abbott et al, 1999).…”

Section: Molecular Genetics Of Lqtsmentioning

confidence: 99%

Pharmacological approach to the treatment of long and short QT syndromes

Patel

Antzelevitch

2008

Pharmacology & Therapeutics

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Inherited channelopathies have received increasing attention in recent years. The past decade has witnessed impressive progress in our understanding of the molecular and cellular basis of arrhythmogenesis associated with inherited channelopathies. An imbalance in ionic forces induced by these channelopathies affects the duration of ventricular repolarization and amplifies the intrinsic electrical heterogeneity of the myocardium, creating an arrhythmogenic milieu. Today, many of the channelopathies have been linked to mutations in specific genes encoding either components of ion channels or membrane or regulatory proteins. Many of the channelopathies are genetically heterogeneous with a variable degree of expression of the disease. Defining the molecular basis of channelopathies can have a profound impact on patient management, particularly in cases in which genotype-specific pharmacotherapy is available.The long QT syndrome (LQTS) is one of the first identified and most studied channelopathies where abnormal prolongation of ventricular repolarization predisposes an individual to life threatening ventricular arrhythmia called Torsade de Pointes. On the other hand of the spectrum, molecular defects favoring premature repolarization lead to Short QT syndrome (SQTS), a recently described inherited channelopathy. Both of these channelopathies are associated with a high risk of sudden cardiac death due to malignant ventricular arrhythmia. Whereas pharmacological therapy is first line treatment for LQTS, defibrillators are considered as primary treatment for SQTS. This review provides a comprehensive review of the molecular genetics, clinical features, genotype-phenotype correlations and genotype-specific approach to pharmacotherapy of these two mirror-image channelopathies, SQTS and LQTS.

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KvLQT1 and IsK (minK) proteins associate to form the IKS cardiac potassium current

Cited by 1,514 publications

References 23 publications

Reconstitution of Muscarinic Modulation of the KCNQ2/KCNQ3 K⁺Channels That Underlie the Neuronal M Current

Reconstitution of Muscarinic Modulation of the KCNQ2/KCNQ3 K⁺Channels That Underlie the Neuronal M Current

Potassium channels in the sinoatrial node and their role in heart rate control

Pharmacological approach to the treatment of long and short QT syndromes

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KvLQT1 and IsK (minK) proteins associate to form the IKS cardiac potassium current

Cited by 1,514 publications

References 23 publications

Reconstitution of Muscarinic Modulation of the KCNQ2/KCNQ3 K+Channels That Underlie the Neuronal M Current

Reconstitution of Muscarinic Modulation of the KCNQ2/KCNQ3 K+Channels That Underlie the Neuronal M Current

Potassium channels in the sinoatrial node and their role in heart rate control

Pharmacological approach to the treatment of long and short QT syndromes

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Product

Resources

About

Reconstitution of Muscarinic Modulation of the KCNQ2/KCNQ3 K⁺Channels That Underlie the Neuronal M Current

Reconstitution of Muscarinic Modulation of the KCNQ2/KCNQ3 K⁺Channels That Underlie the Neuronal M Current