Transcriptional and electrophysiological consequences of KChIP2-mediated regulation of Ca<sub>V</sub>1.2

Thomsen, Morten B.; Foster, Erika; Nguyen, Katherine; Sosunov, Eugene A.

doi:10.4161/chan.3.5.9560

Cited by 17 publications

(20 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, it has become clear that some auxiliary subunits are not exclusively associated with one single pore‐forming unit, but can be part of several different ion–channel complexes. In line with this, we have shown that KChIP2 not only augments Kv4 currents expressed in heterologous cells (Lundby et al 2010) and in cardiomyocytes (Thomsen et al 2009 b ), but also increases native L‐type calcium current ( I Ca,L ) via interaction with the cytosolic N‐terminus of Cav1.2 (Thomsen et al 2009 a , c ; Grubb et al 2012). Cardiac I Ca,L has an essential role in excitation–contraction coupling and the contractile impairment seen in HF is in part secondary to altered cellular calcium handling, resulting in impaired and dyssynchronous calcium release from the sarcoplasmic reticulum (Pogwizd et al 2001), whereas calcium entry via I Ca,L (Bers et al 2006) or channel expression (Marionneau et al 2008) are generally not altered.…”

Section: Introductionsupporting

confidence: 58%

“…Genotyping of mice was performed using tail tips from WT and KChIP2 −/− mice and tissue PCR kit (Extract‐N‐Amp, Sigma‐Aldrich, MO, USA) according to the manufacturer's protocol. PCR was used to amplify KChIP2 and neomycin control using previously published primer sequences (Thomsen et al 2009 a ). The amplified DNA was separated on a 1% agarose gel and visualized with ethidium bromide.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Development of heart failure is independent of K⁺ channel‐interacting protein 2 expression

Speerschneider

Grubb

Metoska

et al. 2013

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

Key points• Previous studies have suggested that the K + channel auxiliary subunit K + channel-interacting protein 2 (KChIP2) serves as a regulator of cardiac remodelling leading to heart failure and increased risk of arrhythmias.• The results presented here show that the progression of cardiac remodelling and heart failure induced by transverse aortic constriction follows a similar time course in wild-type and KChIP2 −/− mice.• Protein expression analysis shows that ventricular KChIP2 is significantly downregulated in heart failure in wild-type mice.• The electrophysiological analysis reveals enlarged J and T wave amplitudes and lower vulnerability to pacing-induced ventricular arrhythmias in KChIP2 −/− control mice compared to wild-type control mice. Heart failure in wild-type and KChIP2 −/− mice prompted comparable prolongation of QT intervals and ventricular effective refractory periods.• Collectively, these results demonstrate that KChIP2 does not influence the structural and functional development of heart failure. Moreover, in contrast to previously reported data, downregulation of KChIP2 expression in heart failure may reduce the risk of cardiac arrhythmia.Abstract Abnormal ventricular repolarization in ion channelopathies and heart disease is a major cause of ventricular arrhythmias and sudden cardiac death. K + channel-interacting protein 2 (KChIP2) expression is significantly reduced in human heart failure (HF), contributing to a loss of the transient outward K + current (I to ). We aim to investigate the possible significance of a changed KChIP2 expression on the development of HF and proarrhythmia. Transverse aortic constrictions (TAC) and sham operations were performed in wild-type (WT) and KChIP2 −/− mice. Echocardiography was performed before and every 2 weeks after the operation. Ten weeks post-surgery, surface ECG was recorded and we paced the heart in vivo to induce arrhythmias. Afterwards, tissue from the left ventricle was used for immunoblotting. Time courses of HF development were comparable in TAC-operated WT and KChIP2 −/− mice. Ventricular protein expression of KChIP2 was reduced by 70% after 10 weeks TAC in WT mice. The amplitudes of the J and T waves were enlarged in KChIP2 −/− control mice. Ventricular effective refractory period, RR, QRS and QT intervals were longer in mice with HF compared to sham-operated mice of either genotype. Pacing-induced ventricular tachycardia (VT) was observed in 5/10 sham-operated WT mice compared with 2/10 HF WT mice with HF. Interestingly, and contrary to previously published data, sham-operated KChIP2 −/− mice were resistant to pacing-induced VT resulting in only 1/10 inducible mice. KChIP2 −/− with HF mice had similar low vulnerability to inducible VT (1/9). Our results suggest that although KChIP2 is downregulated in HF, it is not orchestrating the development of HF. Moreover, KChIP2 affects ventricular repolarization and lowers arrhythmia susceptibility. Hence, downregulation of KChIP2 expression in HF may be antiarrhythmic in mice via reduction of...

show abstract

Section: Introductionsupporting

confidence: 58%

Section: Methodsmentioning

confidence: 99%

Development of heart failure is independent of K⁺ channel‐interacting protein 2 expression

Speerschneider

Grubb

Metoska

et al. 2013

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…For KChIP2, despite its prominent expression in cardiomyocytes, a gene transcription control mechanism similar to the ones involving KChIP3 (DREAM) could not be shown [67]. Rather, KChIP2 has been reported to up-regulate I Ca via a direct interaction with the Cav1.2 protein independently of protein expression or trafficking (see section “Acute modulation of the Kv4/KChIP channel complex by cytoplasmic Ca 2+ ”) [68,69]. Notably, however, it was recently found that in cardiomyocytes KChIP2 acts as a transcritional repressor for certain micro RNAs (miR-34b and miR-34c).…”

Section: Kchips Control Gene Transcriptionmentioning

confidence: 99%

“…It will be interesting to see whether a comparable Kv4/KChIP/Cav nanodomain signaling also exists in other neurons, as suspected recently in the case of Kv4/KChIP/DPP complexes in nociceptive DRG neurons [93], or in cardiomyocytes. Notably, in cardiomyocytes KChIP2 may form a complex with Cav1.2 [68,69], maybe in combination with Kv4 channels. Also, CaMKII, which seems to play a critical role in the Ca 2+ -dependent regulation of Kv4/KChIP channels [22], may participate in this cardiac signaling complex [94–96].…”

Section: Acute Modulation Of the Kv4/kchip Channel Complex By Cytoplamentioning

confidence: 99%

Kv channel-interacting proteins as neuronal and non-neuronal calcium sensors

Bähring

2018

Channels

View full text Add to dashboard Cite

Kv channel-interacting proteins (KChIPs) belong to the neuronal calcium sensor (NCS) family of Ca2+-binding EF-hand proteins. KChIPs constitute a group of specific auxiliary β-subunits for Kv4 channels, the molecular substrate of transient potassium currents in both neuronal and non-neuronal tissues. Moreover, KChIPs can interact with presenilins to control ER calcium signaling and apoptosis, and with DNA to control gene transcription. Ca2+ binding via their EF-hands, with the consequence of conformational changes, is well documented for KChIPs. Moreover, the Ca2+ dependence of the presenilin/KChIP complex may be related to Alzheimer’s disease and the Ca2+ dependence of the DNA/KChIP complex to pain sensing. However, only in few cases could the Ca2+ binding to KChIPs be directly linked to the control of excitability in nerve and muscle cells known to express Kv4/KChIP channel complexes. This review summarizes current knowledge about the Ca2+ binding properties of KChIPs and the Ca2+ dependencies of macromolecular complexes containing KChIPs, including those with presenilins, DNA and especially Kv4 channels. The respective physiological or pathophysiolgical roles of Ca2+ binding to KChIPs are discussed.

show abstract

“…Finally, KChIP2 has recently been demonstrated to alter both transcriptional and electrophysiological properties of the cardiac L-type calcium channel Ca V 1.2. 76,77 While these Ca V 1.2 effects are clearly beyond the scope of our present study, they do provide independent evidence that KChIP2 interaction sites can exist in protein domains outside of the K V 4 N-terminus.…”

Section: Methodsmentioning

confidence: 63%

K_V4.3 N-terminal deletion mutant D2-39

Hovind

Skerritt²,

Campbell³

2011

Channels

View full text Add to dashboard Cite

Transcriptional and electrophysiological consequences of KChIP2-mediated regulation of Ca_V1.2

Cited by 17 publications

References 21 publications

Development of heart failure is independent of K⁺ channel‐interacting protein 2 expression

Development of heart failure is independent of K⁺ channel‐interacting protein 2 expression

Kv channel-interacting proteins as neuronal and non-neuronal calcium sensors

K_V4.3 N-terminal deletion mutant D2-39

Contact Info

Product

Resources

About

Transcriptional and electrophysiological consequences of KChIP2-mediated regulation of CaV1.2

Cited by 17 publications

References 21 publications

Development of heart failure is independent of K+ channel‐interacting protein 2 expression

Development of heart failure is independent of K+ channel‐interacting protein 2 expression

Kv channel-interacting proteins as neuronal and non-neuronal calcium sensors

KV4.3 N-terminal deletion mutant D2-39

Contact Info

Product

Resources

About

Transcriptional and electrophysiological consequences of KChIP2-mediated regulation of Ca_V1.2

Development of heart failure is independent of K⁺ channel‐interacting protein 2 expression

Development of heart failure is independent of K⁺ channel‐interacting protein 2 expression

K_V4.3 N-terminal deletion mutant D2-39