β<sub>2</sub>‐Adrenergic receptor overexpression in the developing mouse heart: evidence for targeted modulation of ion channels

An, Rui-Hai; Heath, Bronagh; Higgins, J. P.; Koch, Walter J.; Lefkowitz, Robert J.; Kass, Robert S.

doi:10.1111/j.1469-7793.1999.019aa.x

Cited by 25 publications

(16 citation statements)

References 49 publications

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“…The fact that isoproterenol significantly exacerbates the differences in these repolarization parameters between Kcnq1 Ϫ/Ϫ and Kcnq1 ϩ/ϩ neonates is consistent with the well-established observation that I Ks is dramatically enhanced by activation of ␤-adrenergic signal transduction pathways (Walsh and Kass, 1988;An et al, 1999;Marx et al, 2002). Our results are also consistent with previous studies showing that pharmacological block of I Ks in canine ventricular "wedge" and myocyte preparations primarily affected repolarization during ␤-adrenergic stimulation (Shimizu and Antzelevitch, 1998;Han et al, 2001).…”

Section: Isoproterenol Exacerbates Long Qt Phenotype In Kcnq1supporting

confidence: 82%

“…In accordance, I Ks is significantly enhanced by ␤-adrenergic stimulation in ventricular myocytes (Walsh and Kass, 1988;An et al, 1999) via a mechanism that appears to require phosphorylation of the KCNQ1 channel by protein kinase A (PKA) (Marx et al, 2002). Thus, the absence of I Ks may compromise ventricular repolarization primarily during sympathetic activation.…”

mentioning

confidence: 77%

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Isoproterenol Exacerbates a Long QT Phenotype in Kcnq1-Deficient Neonatal Mice: Possible Roles for Human-Like Kcnq1 Isoform 1 and Slow Delayed Rectifier K⁺ Current

Knollmann

Casimiro²,

Katchman³

et al. 2004

J Pharmacol Exp Ther

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To determine whether the neonatal mouse can serve as a useful model for studying the molecular pharmacological basis of Long QT Syndrome Type 1 (LQT1), which has been linked to mutations in the human KCNQ1 gene, we measured QT intervals from electrocardiogram (ECG) recordings of wild-type (WT) and Kcnq1 knockout (KO) neonates before and after injection with the ␤-adrenergic receptor agonist, isoproterenol (0.17 mg/ kg, i.p.). Modest but significant increases in JT, QT, and ratecorrected QT (QTc) intervals were found in KO neonates relative to WT siblings during baseline ECG assessments (QTc ϭ 57 Ϯ 3 ms, n ϭ 22 versus 49 Ϯ 2 ms, n ϭ 28, respectively, p Ͻ 0.05). Moreover, JT, QT, and QTc intervals significantly increased following isoproterenol challenge in the KO (p Ͻ 0.01) but not the WT group (p ϭ 0.57). Furthermore, whole-cell patch-clamp recordings show that the slow delayed rectifier K ϩ current (I Ks ) was absent in KO but present in WT myocytes, where it was strongly enhanced by isoproterenol. This finding was confirmed by showing that the selective I Ks inhibitor, L-735,821, blocked I Ks and prolonged action potential duration in WT but not KO hearts. These data demonstrate that disruption of the Kcnq1 gene leads to loss of I Ks , resulting in a long QT phenotype that is exacerbated by ␤-adrenergic stimulation. This phenotype closely reflects that observed in human LQT1 patients, suggesting that the neonatal mouse serves as a valid model for this condition. This idea is further supported by new RNA data showing that there is a high degree of homology (Ͼ88% amino acid identity) between the predominant human and mouse cardiac Kcnq1 isoforms.

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Section: Isoproterenol Exacerbates Long Qt Phenotype In Kcnq1supporting

confidence: 82%

mentioning

confidence: 77%

Isoproterenol Exacerbates a Long QT Phenotype in Kcnq1-Deficient Neonatal Mice: Possible Roles for Human-Like Kcnq1 Isoform 1 and Slow Delayed Rectifier K⁺ Current

Knollmann

Casimiro²,

Katchman³

et al. 2004

J Pharmacol Exp Ther

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“…Differences in phosphorylation were also demonstrated between K and Ca channels involving the contribution of more than one protein kinase (Hartzell et al 1995). Recently subcellular compartmentalization of cAMP resulting in differences in cAMP-dependent modulation of Ca and K channels were reported (An et al 1999). Any of these mechanisms may explain why I Ca could be suppressed by ET-1 in untreated myocytes, while inhibition of I K required previous application of isoproterenol.…”

Section: Discussionmentioning

confidence: 92%

Different effects of endothelin-1 on calcium and potassium currents in canine ventricular cells

Bányász

Magyar

Körtvély

et al. 2001

Naunyn-Schmiedeberg's Archives of Pharmacology

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Effects of endothelin-1 (ET-1) on the L-type calcium current (ICa) and delayed rectifier potassium current (IK) were studied in isolated canine ventricular cardiomyocytes using the whole-cell configuration of the patch-clamp technique. ET-1 (8 nM) was applied in three experimental arrangements: untreated cells, in the presence of 50 nM isoproterenol, and in the presence of 250 microM 8-bromo-cAMP. In untreated cells, ET-1 significantly decreased the peak amplitude of ICa by 32.3+/-4.8% at +5 mV (P<0.05) without changing activation or inactivation characteristics of ICa. ET-1 had no effect on the amplitude of IK, Ito (transient outward current) or IK1 (inward rectifier K current) in untreated cells; however, the time course of recovery from inactivation of Ito was significantly increased by ET-1 (from 26.5+/-4.6 ms to 59.5+/- 1.8 ms, P < 0.05). Amplitude and time course of intracellular calcium transients, recorded in voltage-clamped cells previously loaded with the fluorescent calcium indicator dye Fura-2, were not affected by ET-1. ET-1 had no effect on force of contraction in canine ventricular trabeculae. Isoproterenol increased the amplitude of ICa to 263+/-29% of control. ET-1 reduced ICa also in isoproterenol-treated cells by 17.8+/-2% (P<0.05); this inhibition was significantly less than obtained in untreated cells. IK was increased by isoproterenol to 213+/-18% of control. This effect of isoproterenol on IK was reduced by 31.8+/-4.8% if the cells were pretreated with ET-1. Similarly, in isoproterenol-treated cells ET-1 decreased IK by 16.2+/-1.5% (P<0.05). Maximal activation of protein kinase A (PKA) was achieved by application of 8-bromo-cAMP in the pipette solution. In the presence of 8-bromo-cAMP ET-1 failed to alter ICa or IK It was concluded that differences in effects of ET-1 on ICa and IK may be related to differences in cAMP sensitivity of the currents.

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“…Such selectivity would require spatially restricted cAMP signals. Stimulation of either β 1 or β 2 ARs leads to increased Ca 2+ influx through Ca v 1.2 into ventricular cardiomyocytes (5, 20, 441). However, only β 1 but not β 2 AR activation effectively stimulates PKA throughout the myocyte resulting in a global phosphorylation of phospholamban to foster Ca 2+ sequestration in the sarcoplasmic reticulum, glycogen phosphorylase kinase to regulate glycogen hydrolysis, and troponins I and C to control contraction and relaxation (441).…”

Section: Regulation Of Ion Channels By Protein Kinase Amentioning

confidence: 99%

Supramolecular Assemblies and Localized Regulation of Voltage-Gated Ion Channels

Dai¹,

Hall²,

Hell³

2009

Physiological Reviews

308

299

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This review addresses the localized regulation of voltage-gated ion channels by phosphorylation. Comprehensive data on channel regulation by associated protein kinases, phosphatases, and related regulatory proteins are mainly available for voltage-gated Ca2+ channels, which form the main focus of this review. Other voltage-gated ion channels and especially Kv7.1-3 (KCNQ1-3), the large- and small-conductance Ca2+-activated K+ channels BK and SK2, and the inward-rectifying K+ channels Kir3 have also been studied to quite some extent and will be included. Regulation of the L-type Ca2+ channel Cav1.2 by PKA has been studied most thoroughly as it underlies the cardiac fight-or-flight response. A prototypical Cav1.2 signaling complex containing the β2 adrenergic receptor, the heterotrimeric G protein Gs, adenylyl cyclase, and PKA has been identified that supports highly localized via cAMP. The type 2 ryanodine receptor as well as AMPA- and NMDA-type glutamate receptors are in close proximity to Cav1.2 in cardiomyocytes and neurons, respectively, yet independently anchor PKA, CaMKII, and the serine/threonine phosphatases PP1, PP2A, and PP2B, as is discussed in detail. Descriptions of the structural and functional aspects of the interactions of PKA, PKC, CaMKII, Src, and various phosphatases with Cav1.2 will include comparisons with analogous interactions with other channels such as the ryanodine receptor or ionotropic glutamate receptors. Regulation of Na+ and K+ channel phosphorylation complexes will be discussed in separate papers. This review is thus intended for readers interested in ion channel regulation or in localization of kinases, phosphatases, and their upstream regulators.

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β₂‐Adrenergic receptor overexpression in the developing mouse heart: evidence for targeted modulation of ion channels

Cited by 25 publications

References 49 publications

Isoproterenol Exacerbates a Long QT Phenotype in Kcnq1-Deficient Neonatal Mice: Possible Roles for Human-Like Kcnq1 Isoform 1 and Slow Delayed Rectifier K⁺ Current

Isoproterenol Exacerbates a Long QT Phenotype in Kcnq1-Deficient Neonatal Mice: Possible Roles for Human-Like Kcnq1 Isoform 1 and Slow Delayed Rectifier K⁺ Current

Different effects of endothelin-1 on calcium and potassium currents in canine ventricular cells

Supramolecular Assemblies and Localized Regulation of Voltage-Gated Ion Channels

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β2‐Adrenergic receptor overexpression in the developing mouse heart: evidence for targeted modulation of ion channels

Cited by 25 publications

References 49 publications

Isoproterenol Exacerbates a Long QT Phenotype in Kcnq1-Deficient Neonatal Mice: Possible Roles for Human-Like Kcnq1 Isoform 1 and Slow Delayed Rectifier K+ Current

Isoproterenol Exacerbates a Long QT Phenotype in Kcnq1-Deficient Neonatal Mice: Possible Roles for Human-Like Kcnq1 Isoform 1 and Slow Delayed Rectifier K+ Current

Different effects of endothelin-1 on calcium and potassium currents in canine ventricular cells

Supramolecular Assemblies and Localized Regulation of Voltage-Gated Ion Channels

Contact Info

Product

Resources

About

β₂‐Adrenergic receptor overexpression in the developing mouse heart: evidence for targeted modulation of ion channels

Isoproterenol Exacerbates a Long QT Phenotype in Kcnq1-Deficient Neonatal Mice: Possible Roles for Human-Like Kcnq1 Isoform 1 and Slow Delayed Rectifier K⁺ Current

Isoproterenol Exacerbates a Long QT Phenotype in Kcnq1-Deficient Neonatal Mice: Possible Roles for Human-Like Kcnq1 Isoform 1 and Slow Delayed Rectifier K⁺ Current