Dynamic control of hERG/IKr by PKA-mediated interactions with 14-3-3

Anna Kagan, Thomas V. McDonald

Research output: Chapter in Book/Report/Conference proceedingConference contribution

11 Citations (Scopus)

Abstract

IKs has been considered the potassium current most responsible for adrenergic/cAMP-mediated changes in cardiac repolarization during stress. Increasing biochemical, electrophysiological and genetic evidence however, points to a role for hERG/IKr in β-adrenergic responses. Elevations of cAMP as seen in β-adrenergic stimulation can result in PKA-dependent phosphorylation of hERG and direct binding of cAMP to the channel protein. Generally, there is a suppression of current density due to the channel phosphorylation. We recently identified a novel protein-protein interaction between hERG and the adaptor protein 14-3-3ε. Interaction sites exist on both N- and C-termini of hERG and the interaction is dynamic, requiring phosphorylation of the channel by PKA. When both sites bind to 14-3-3 proteins there is an acceleration and augmentation of current activation in contrast to the depression of current with phosphorylation alone. When sufficient 14-3-3 is available the phosphorylation state of the channel is stabilized and prolonged. Thus, 14-3-3 interactions with hERG provide a unique mechanism for plasticity in the autonomic control of stress-dependent regulation of cardiac membrane excitability. Here, we summarize our findings and report on our further efforts to analyse interactions between the native channel protein and 14-3-3 in cardiac myocytes.

Original languageEnglish (US)
Title of host publicationNovartis Foundation Symposium
Pages75-89
Number of pages15
Volume266
StatePublished - 2005

Publication series

NameNovartis Foundation Symposium
Volume266
ISSN (Print)15282511

Fingerprint

14-3-3 Proteins
Phosphorylation
Adrenergic Agents
Proteins
Cardiac Myocytes
Molecular Biology
Potassium
Membranes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kagan, A., & McDonald, T. V. (2005). Dynamic control of hERG/IKr by PKA-mediated interactions with 14-3-3. In Novartis Foundation Symposium (Vol. 266, pp. 75-89). (Novartis Foundation Symposium; Vol. 266).

Dynamic control of hERG/IKr by PKA-mediated interactions with 14-3-3. / Kagan, Anna; McDonald, Thomas V.

Novartis Foundation Symposium. Vol. 266 2005. p. 75-89 (Novartis Foundation Symposium; Vol. 266).

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Kagan, A & McDonald, TV 2005, Dynamic control of hERG/IKr by PKA-mediated interactions with 14-3-3. in Novartis Foundation Symposium. vol. 266, Novartis Foundation Symposium, vol. 266, pp. 75-89.
Kagan A, McDonald TV. Dynamic control of hERG/IKr by PKA-mediated interactions with 14-3-3. In Novartis Foundation Symposium. Vol. 266. 2005. p. 75-89. (Novartis Foundation Symposium).
Kagan, Anna ; McDonald, Thomas V. / Dynamic control of hERG/IKr by PKA-mediated interactions with 14-3-3. Novartis Foundation Symposium. Vol. 266 2005. pp. 75-89 (Novartis Foundation Symposium).
@inproceedings{892e8c631df3432991b6b8a0afbe8250,
title = "Dynamic control of hERG/IKr by PKA-mediated interactions with 14-3-3",
abstract = "IKs has been considered the potassium current most responsible for adrenergic/cAMP-mediated changes in cardiac repolarization during stress. Increasing biochemical, electrophysiological and genetic evidence however, points to a role for hERG/IKr in β-adrenergic responses. Elevations of cAMP as seen in β-adrenergic stimulation can result in PKA-dependent phosphorylation of hERG and direct binding of cAMP to the channel protein. Generally, there is a suppression of current density due to the channel phosphorylation. We recently identified a novel protein-protein interaction between hERG and the adaptor protein 14-3-3ε. Interaction sites exist on both N- and C-termini of hERG and the interaction is dynamic, requiring phosphorylation of the channel by PKA. When both sites bind to 14-3-3 proteins there is an acceleration and augmentation of current activation in contrast to the depression of current with phosphorylation alone. When sufficient 14-3-3 is available the phosphorylation state of the channel is stabilized and prolonged. Thus, 14-3-3 interactions with hERG provide a unique mechanism for plasticity in the autonomic control of stress-dependent regulation of cardiac membrane excitability. Here, we summarize our findings and report on our further efforts to analyse interactions between the native channel protein and 14-3-3 in cardiac myocytes.",
author = "Anna Kagan and McDonald, {Thomas V.}",
year = "2005",
language = "English (US)",
isbn = "9780470021408",
volume = "266",
series = "Novartis Foundation Symposium",
pages = "75--89",
booktitle = "Novartis Foundation Symposium",

}

TY - GEN

T1 - Dynamic control of hERG/IKr by PKA-mediated interactions with 14-3-3

AU - Kagan, Anna

AU - McDonald, Thomas V.

PY - 2005

Y1 - 2005

N2 - IKs has been considered the potassium current most responsible for adrenergic/cAMP-mediated changes in cardiac repolarization during stress. Increasing biochemical, electrophysiological and genetic evidence however, points to a role for hERG/IKr in β-adrenergic responses. Elevations of cAMP as seen in β-adrenergic stimulation can result in PKA-dependent phosphorylation of hERG and direct binding of cAMP to the channel protein. Generally, there is a suppression of current density due to the channel phosphorylation. We recently identified a novel protein-protein interaction between hERG and the adaptor protein 14-3-3ε. Interaction sites exist on both N- and C-termini of hERG and the interaction is dynamic, requiring phosphorylation of the channel by PKA. When both sites bind to 14-3-3 proteins there is an acceleration and augmentation of current activation in contrast to the depression of current with phosphorylation alone. When sufficient 14-3-3 is available the phosphorylation state of the channel is stabilized and prolonged. Thus, 14-3-3 interactions with hERG provide a unique mechanism for plasticity in the autonomic control of stress-dependent regulation of cardiac membrane excitability. Here, we summarize our findings and report on our further efforts to analyse interactions between the native channel protein and 14-3-3 in cardiac myocytes.

AB - IKs has been considered the potassium current most responsible for adrenergic/cAMP-mediated changes in cardiac repolarization during stress. Increasing biochemical, electrophysiological and genetic evidence however, points to a role for hERG/IKr in β-adrenergic responses. Elevations of cAMP as seen in β-adrenergic stimulation can result in PKA-dependent phosphorylation of hERG and direct binding of cAMP to the channel protein. Generally, there is a suppression of current density due to the channel phosphorylation. We recently identified a novel protein-protein interaction between hERG and the adaptor protein 14-3-3ε. Interaction sites exist on both N- and C-termini of hERG and the interaction is dynamic, requiring phosphorylation of the channel by PKA. When both sites bind to 14-3-3 proteins there is an acceleration and augmentation of current activation in contrast to the depression of current with phosphorylation alone. When sufficient 14-3-3 is available the phosphorylation state of the channel is stabilized and prolonged. Thus, 14-3-3 interactions with hERG provide a unique mechanism for plasticity in the autonomic control of stress-dependent regulation of cardiac membrane excitability. Here, we summarize our findings and report on our further efforts to analyse interactions between the native channel protein and 14-3-3 in cardiac myocytes.

UR - http://www.scopus.com/inward/record.url?scp=23844524895&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=23844524895&partnerID=8YFLogxK

M3 - Conference contribution

C2 - 16050263

AN - SCOPUS:23844524895

SN - 9780470021408

VL - 266

T3 - Novartis Foundation Symposium

SP - 75

EP - 89

BT - Novartis Foundation Symposium

ER -