| Property | Value |
|---|
| Working Groups |  AG Maier,  AG Nikolaev |
| Subproject | A01, A03 |
| Open Access |  Yes |
| Publication Type | Journal Article |
| Peer Reviewed | Unknown |
| PMID |  24812278 |
| DOI |  10.1093/cvr/cvu120 |
| Publication Year | 2014 |
| Title | Tubulin polymerization disrupts cardiac β-adrenergic regulation of late INa  |
| Journal | Cardiovascular Research |
| ISSN | 0008-6363 |
| eISSN | 1755-3245 |
| URL | http://cardiovascres.oxfordjournals.org/content/early/2014/05/08/cvr.cvu120 |
| Pages | cvu120 |
| Journal Abbreviation | Cardiovasc Res |
| Extra | Aims The anticancer drug paclitaxel (TXL) that polymerizes microtubules is associated with arrhythmias and sinus node dysfunction. TXL can alter membrane expression of Na channels (NaV1.5) and Na current (INa) but the mechanisms are unknown. Ca/CaM-dependent protein kinase II (CaMKII) can be activated by β-adrenergic stimulation and regulates INa gating. We tested, whether TXL interferes with isoproterenol (ISO)-induced activation of CaMKII and consequent INa regulation. Methods and Results In wild-type (WT) mouse myocytes, the addition of ISO (1 µmol/L) resulted in increased CaMKII autophosphorylation (Western blotting). This increase was completely abolished after pre-treatment with TXL (100 µmol/L, 1.5 h). The mechanism was further investigated in human embryonic kidney cells. TXL inhibited the ISO-induced β-arrestin translocation. Interestingly, both knockdown of β-arrestin 2 expression using small interfering RNA or inhibition of exchange protein directly activated by cAMP (Epac) blocked the ISO-induced CaMKII autophosphorylation similar to TXL. The generation of cAMP, however, was unaltered (Epac1-camps). CaMKII-dependent Na channel function was measured using patch-clamp technic in isolated cardiomyoctes. ISO stimulation failed to induce CaMKII-dependent enhancement of late INa and Na channel inactivation (negative voltage shift in steady-state activation and enhanced intermediate inactivation) after TXL pre-incubation. Consistent with this, TXL also inhibited ISO-induced CaMKII-specific Na channel phosphorylation (at serine 571 of NaV1.5). Conclusion TXL preincubation disrupts the ISO-dependent CaMKII activation and consequent Na channel regulation. This may be important for patients receiving TXL treatments but also relevant for conditions of increased CaMKII expression and enhanced β-adrenergic stimulation like in heart failure. PMID: 24812278 |
| Authors | Dybkova N, Wagner S, Backs J, Hund TJ, Mohler PJ, Sowa T, Nikolaev VO, Maier LS |
| First Author | Dybkova N |
| Last Author | Maier LS |
| Scholia |  Wikidata-based representation at Scholia |
External Resources
academic...20.pdfhttps://academic.oup.com/cardiovascres/article-pdf/103/1/168/17235914/cvu120.pdf
Article fulltext
gro-2/32981http://resolver.sub.uni-goettingen.de/purl?gro-2/32981
GRO.publications identifier
10090https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=10090
NCBI Taxonomy (Mus musculus)
0000-0002-7529-5179https://orcid.org/0000-0002-7529-5179
ORCID identifier (Viacheslav O. Nikolaev)
0000-0001-9915-4429https://orcid.org/0000-0001-9915-4429
ORCID identifier (Lars S. Maier)
031t5w623https://ror.org/031t5w623
ROR identifier (031t5w623, German Centre for Cardiovascular Research)
021ft0n22https://ror.org/021ft0n22
ROR identifier (021ft0n22, University Medical Center Göttingen)
SCR_003070https://scicrunch.org/resolver/SCR_003070
SciCrunch identifier (RRID:SCR_003070, ImageJ)
academic...486411https://academic.oup.com/cardiovascres/article/103/1/168/2931007#85486411
Supplemental material
Q34048285https://www.wikidata.org/wiki/Q34048285
Wikidata ID
