KCNE2 modulates current amplitudes and activation kinetics of HCN4: influence of KCNE family members on HCN4 currents

Decher, Niels; Bundis, Florian; Vajna, Rolf; Steinmeyer, Klaus

doi:10.1007/s00424-003-1127-7

Cited by 90 publications

(93 citation statements)

References 39 publications

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“…a dependence on conditioning mechanisms such as phosphorylation of the channel protein or the interaction with auxiliary/cytoskeletal proteins. Phosphorylation-dependent processes, for example, can modify channel kinetics (33) and the density of expressed channels (34); also, it has been shown recently that HCN channels are modulated by interaction with the KCNE2 subunit (35,36), even though the relevance of this interaction is still uncertain (32). The existence of a "context" dependence of HCN properties is further supported by evidence that some of the kinetic features of a given isoform vary in different expression systems (37).…”

Section: Resultsmentioning

confidence: 98%

Interaction of the Pacemaker Channel HCN1 with Filamin A

Gravante

Barbuti

Milanesi

et al. 2004

Journal of Biological Chemistry

109

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Pacemaker channels are encoded by the HCN gene family and are responsible for a variety of cellular functions including control of spontaneous activity in cardiac myocytes and control of excitability in different types of neurons. Some of these functions require specific membrane localization. Although several voltagegated channels are known to interact with intracellular proteins exerting auxiliary functions, no cytoplasmic proteins have been found so far to modulate HCN channels. Through the use of a yeast two-hybrid technique, here we showed that filamin A interacts with HCN1, an HCN isoform widely expressed in the brain, but not with HCN2 or HCN4. Filamin A is a cytoplasmic scaffold protein with actin-binding domains whose main function is to link transmembrane proteins to the actin cytoskeleton. Using several HCN1 C-terminal constructs, we identified a filamin A-interacting region of 22 amino acids located downstream from the cyclic nucleotide-binding domain; this region is not conserved in HCN2, HCN3, or HCN4. We also verified by immunoprecipitation from bovine brain that the filamin A-HCN1 interaction is functional in vivo. In filamin A-expressing cells (filamin ؉ ), HCN1 (but not HCN4) channels were expressed in hot spots, whereas they were evenly distributed on the membrane of cells lacking filamin A (filamin ؊ ) indicating that interaction with filamin A affects membrane localization. Also, in filamin ؊ cells the gating kinetics of HCN1 were strongly accelerated relative to filamin ؉ cells. The interaction with filamin A may contribute to localizing HCN1 channels to specific neuronal areas and to modulating channel activity.

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Section: Resultsmentioning

confidence: 98%

Interaction of the Pacemaker Channel HCN1 with Filamin A

Gravante

Barbuti

Milanesi

et al. 2004

Journal of Biological Chemistry

109

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“…The dominant HCN isoform in the sinoatrial node is HCN4 (9, 17), which activates too slowly when expressed in heterologous systems (17,18) to recapitulate the native sinoatrial node pacemaker current. A heterologous expression study confirmed that MiRP1 co-expression increases HCN4 current magnitude but found that activation kinetics slowed further in the presence of MiRP1 (5). Ultimate resolution of the question of MiRP1-HCN interactions in the sinoatrial node and the extent to which this contributes to the activation kinetics of native pacemaker current in this tissue await future studies that suppress or reduce MiRP1 expression within the node and determine the impact on the endogenous pacemaker current.…”

Section: Discussionmentioning

confidence: 93%

“…Thus, the structure-function relation of MiRP1 and HCN proteins and the mechanism of action by which MiRP1 modulates HCN function remain to be determined. The observations that MinK is ineffective at altering HCN function (4) and that its C-terminal does not interact with HCN in a yeast two-hybrid analysis (5) suggest that a MinK/MiRP1 chimeric approach might provide insights into the critical residues involved.…”

Section: Discussionmentioning

confidence: 99%

MiRP1 Modulates HCN2 Channel Expression and Gating in Cardiac Myocytes

Qu¹,

Kryukova²,

Potapova

et al. 2004

Journal of Biological Chemistry

119

106

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MinK-related protein (MiRP1 or KCNE2) interacts with the hyperpolarization-activated, cyclic nucleotidegated (HCN) family of pacemaker channels to alter channel gating in heterologous expression systems. Given the high expression levels of MiRP1 and HCN subunits in the cardiac sinoatrial node and the contribution of pacemaker channel function to impulse initiation in that tissue, such an interaction could be of considerable physiological significance. However, the functional evidence for MiRP1/HCN interactions in heterologous expression studies has been accompanied by inconsistencies between studies in terms of the specific effects on channel function. To evaluate the effect of MiRP1 on HCN expression and function in a physiological context, we used an adenovirus approach to overexpress a hemagglutinin (HA)-tagged MiRP1 (HAMiRP1) and HCN2 in neonatal rat ventricular myocytes, a cell type that expresses both MiRP1 and HCN2 message at low levels. HA-MiRP1 co-expression with HCN2 resulted in a 4-fold increase in maximal conductance of pacemaker currents compared with HCN2 expression alone. HCN2 activation and deactivation kinetics also changed, being significantly more rapid for voltages between ؊60 and ؊95 mV when HA-MiRP1 was co-expressed with HCN2. However, the voltage dependence of activation was not affected. Co-immunoprecipitation experiments demonstrated that expressed HA-MiRP1 and HCN2, as well as endogenous MiRP1 and HCN2, co-assemble in ventricular myocytes. The results indicate that MiRP1 acts as a ␤ subunit for HCN2 pacemaker channel subunits and alters channel gating at physiologically relevant voltages in cardiac cells.MinK-related protein (MiRP1 or KCNE2) is purported to be a ␤ subunit for several voltage-gated potassium channels, including the rapid delayed rectifier (1), slow delayed rectifier (2), and transient outward current (3). In addition, we have reported that it can act as a ␤ subunit for the hyperpolarizationactivated, cyclic nucleotide-gated (HCN) 1 family of pacemaker channels (4). We found that co-expression of MiRP1 with HCN1 or HCN2 in Xenopus oocytes resulted in larger and more rapidly activating currents than when either HCN isoform was expressed alone but that MiRP1 did not shift the midpoint of activation of either isoform. Further, co-immunoprecipitation experiments involving HA-tagged MiRP1 and HCN1 demonstrated that the two proteins interact when co-expressed in oocytes.A more recent study demonstrated MiRP1 interaction with the HCN4 isoform. Here, co-expression with MiRP1, either in oocytes or Chinese hamster ovary cells, also resulted in increased current amplitude, but this was associated with slowing of kinetics and a negative shift of the midpoint of activation (5). However, another laboratory did not detect any effect of MiRP1 when co-expressed in HEK293 cells with either HCN4 or an HCN1-HCN4 tandem construct (6). Finally, a study of MiRP1 and HCN2 co-expression in Chinese hamster ovary cells reported a reduced time-dependent current component and increased instantaneous ...

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“…The β accessory subunit MiRP1 changes the activation kinetics of the current in opposite ways depending on the HCN isoform. Although it has been reported to increase the activation kinetics and the currents of HCN1 and 2 [43,44] , it decreases the activation kinetics but increases the I f current when it is associated with HCN4 [45] . Other HCN regulatory mechanism have been described, including phosphatidylinositol 4,5-bisphosphate (PIP 2 ) modulation [46] or the direct actions of kinases [47] and phosphatases [48,49] .…”

Section: Membrane or Voltage Clock Modelmentioning

confidence: 91%

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

et al. 2016

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The proper expression and function of the cardiac pacemaker is a critical feature of heart physiology. The sinoatrial node (SAN) in human right atrium generates an electrical stimulation approximately 70 times per minute, which propagates from a conductive network to the myocardium leading to chamber contractions during the systoles. Although the SAN and other nodal conductive structures were identified more than a century ago, the mechanisms involved in the generation of cardiac automaticity remain highly debated. In this short review, we survey the current data related to the development of the human cardiac conduction system and the various mechanisms that have been proposed to underlie the pacemaker activity. We also present the human embryonic stem cellderived cardiomyocyte system, which is used as a model for studying the pacemaker. Finally, we describe our latest characterization of the previously unrecognized role of the SK4 Ca 2+ -activated K + channel conductance in pacemaker cells. By exquisitely balancing the inward currents during the diastolic depolarization, the SK4 channels appear to play a crucial role in human cardiac automaticity.

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KCNE2 modulates current amplitudes and activation kinetics of HCN4: influence of KCNE family members on HCN4 currents

Cited by 90 publications

References 39 publications

Interaction of the Pacemaker Channel HCN1 with Filamin A

Interaction of the Pacemaker Channel HCN1 with Filamin A

MiRP1 Modulates HCN2 Channel Expression and Gating in Cardiac Myocytes

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

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