The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through Gβγ-mediated L-type calcium current disinhibition
Rationale: - - The Gβγ-sequestering peptide β-adrenergic receptor kinase (βARK)ct derived from the G-protein-coupled receptor kinase (GRK)2 carboxyl terminus has emerged as a promising target for gene-based heart failure therapy. Enhanced downstream cAMP signaling has been proposed as the underlyin...
Gespeichert in:
| Hauptverfasser: | , , , , , , , , , , , , , , , , |
|---|---|
| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2011
|
| In: |
Circulation research
Year: 2011, Jahrgang: 108, Heft: 1, Pages: 27-39 |
| ISSN: | 1524-4571 |
| DOI: | 10.1161/CIRCRESAHA.110.225201 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1161/CIRCRESAHA.110.225201 Verlag, lizenzpflichtig, Volltext: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.110.225201 
|
| Verfasserangaben: | Mirko Völkers, Christian Weidenhammer, Nicole Herzog, Gang Qiu, Kristin Spaich, Frederic von Wegner, Karsten Peppel, Oliver J. Müller, Stefanie Schinkel, Joseph E. Rabinowitz, Hans-Jörg Hippe, Henriette Brinks, Hugo A. Katus, Walter J. Koch, Andrea D. Eckhart, Oliver Friedrich, Patrick Most |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1819880524 | ||
| 003 | DE-627 | ||
| 005 | 20230710105224.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 221025s2011 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1161/CIRCRESAHA.110.225201 |2 doi | |
| 035 | |a (DE-627)1819880524 | ||
| 035 | |a (DE-599)KXP1819880524 | ||
| 035 | |a (OCoLC)1389762474 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Völkers, Mirko |d 1978- |e VerfasserIn |0 (DE-588)133026442 |0 (DE-627)530939932 |0 (DE-576)299573753 |4 aut | |
| 245 | 1 | 4 | |a The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through Gβγ-mediated L-type calcium current disinhibition |c Mirko Völkers, Christian Weidenhammer, Nicole Herzog, Gang Qiu, Kristin Spaich, Frederic von Wegner, Karsten Peppel, Oliver J. Müller, Stefanie Schinkel, Joseph E. Rabinowitz, Hans-Jörg Hippe, Henriette Brinks, Hugo A. Katus, Walter J. Koch, Andrea D. Eckhart, Oliver Friedrich, Patrick Most |
| 246 | 3 | 3 | |a The inotropic peptide beta ARKct improves beta AR responsiveness in normal and failing cardiomyocytes through G beta upsilon -mediated L-type calcium current disinhibition |
| 246 | 3 | 3 | |a The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through G βγ-mediated L-type calcium current disinhibition |
| 264 | 1 | |c 2011 | |
| 300 | |a 13 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Ursprünglich veröffentlicht Version 1: 24 Nov 2010 | ||
| 500 | |a Im Text ist "βγ" tiefgestellt | ||
| 500 | |a Gesehen am 25.10.2022 | ||
| 520 | |a Rationale: - - The Gβγ-sequestering peptide β-adrenergic receptor kinase (βARK)ct derived from the G-protein-coupled receptor kinase (GRK)2 carboxyl terminus has emerged as a promising target for gene-based heart failure therapy. Enhanced downstream cAMP signaling has been proposed as the underlying mechanism for increased β-adrenergic receptor (βAR) responsiveness. However, molecular targets mediating improved cardiac contractile performance by βARKct and its impact on Gβγ-mediated signaling have yet to be fully elucidated. - - Objective: - - We sought to identify Gβγ-regulated targets and signaling mechanisms conveying βARKct-mediated enhanced βAR responsiveness in normal (NC) and failing (FC) adult rat ventricular cardiomyocytes. - - Methods and Results: - - Assessing viral-based βARKct gene delivery with electrophysiological techniques, analysis of contractile performance, subcellular Ca2+ handling, and site-specific protein phosphorylation, we demonstrate that βARKct enhances the cardiac L-type Ca2+ channel (LCC) current (ICa) both in NCs and FCs on βAR stimulation. Mechanistically, βARKct augments ICa by preventing enhanced inhibitory interaction between the α1-LCC subunit (Cav1.2α) and liberated Gβγ subunits downstream of activated βARs. Despite improved βAR contractile responsiveness, βARKct neither increased nor restored cAMP-dependent protein kinase (PKA) and calmodulin-dependent kinase II signaling including unchanged protein kinase (PK)Cε, extracellular signal-regulated kinase (ERK)1/2, Akt, ERK5, and p38 activation both in NCs and FCs. Accordingly, although βARKct significantly increases ICa and Ca2+ transients, being susceptible to suppression by recombinant Gβγ protein and use-dependent LCC blocker, βARKct-expressing cardiomyocytes exhibit equal basal and βAR-stimulated sarcoplasmic reticulum Ca2+ load, spontaneous diastolic Ca2+ leakage, and survival rates and were less susceptible to field-stimulated Ca2+ waves compared with controls. - - Conclusion: - - Our study identifies a Gβγ-dependent signaling pathway attenuating cardiomyocyte ICa on βAR as molecular target for the Gβγ-sequestering peptide βARKct. Targeted interruption of this inhibitory signaling pathway by βARKct confers improved βAR contractile responsiveness through increased ICa without enhancing regular or restoring abnormal cAMP-signaling. βARKct-mediated improvement of ICa rendered cardiomyocytes neither susceptible to βAR-induced damage nor arrhythmogenic sarcoplasmic reticulum Ca2+ leakage. | ||
| 650 | 4 | |a G proteins | |
| 650 | 4 | |a L-type Ca2+ channel | |
| 650 | 4 | |a β-adrenergic receptor | |
| 650 | 4 | |a βARKct | |
| 700 | 1 | |a Weidenhammer, Christian |e VerfasserIn |4 aut | |
| 700 | 1 | |a Herzog, Nicole |e VerfasserIn |4 aut | |
| 700 | 1 | |a Qiu, Gang |e VerfasserIn |4 aut | |
| 700 | 1 | |a Spaich, Kristin |e VerfasserIn |4 aut | |
| 700 | 1 | |a von Wegner, Frederic |e VerfasserIn |4 aut | |
| 700 | 1 | |a Peppel, Karsten |e VerfasserIn |4 aut | |
| 700 | 1 | |a Müller, Oliver J. |d 1971- |e VerfasserIn |0 (DE-588)121693449 |0 (DE-627)705619621 |0 (DE-576)292833504 |4 aut | |
| 700 | 1 | |a Schinkel, Stefanie |e VerfasserIn |4 aut | |
| 700 | 1 | |a Rabinowitz, Joseph E. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Hippe, Hans-Jörg |d 1970- |e VerfasserIn |0 (DE-588)130878588 |0 (DE-627)507232011 |0 (DE-576)173677991 |4 aut | |
| 700 | 1 | |a Brinks, Henriette |e VerfasserIn |4 aut | |
| 700 | 1 | |a Katus, Hugo |d 1951- |e VerfasserIn |0 (DE-588)108916618 |0 (DE-627)577155040 |0 (DE-576)289625076 |4 aut | |
| 700 | 1 | |a Koch, Walter J. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Eckhart, Andrea D. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Friedrich, Oliver |e VerfasserIn |4 aut | |
| 700 | 1 | |a Most, Patrick |d 1969- |e VerfasserIn |0 (DE-588)124606431 |0 (DE-627)363440267 |0 (DE-576)29440919X |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Circulation research |d New York, NY : Assoc., 1953 |g 108(2011), 1 vom: 7. Jan., Seite 27-39 |h Online-Ressource |w (DE-627)266880126 |w (DE-600)1467838-X |w (DE-576)075145766 |x 1524-4571 |7 nnas |a The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through Gβγ-mediated L-type calcium current disinhibition |
| 773 | 1 | 8 | |g volume:108 |g year:2011 |g number:1 |g day:7 |g month:01 |g pages:27-39 |g extent:13 |a The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through Gβγ-mediated L-type calcium current disinhibition |
| 856 | 4 | 0 | |u https://doi.org/10.1161/CIRCRESAHA.110.225201 |x Verlag |x Resolving-System |z lizenzpflichtig |3 Volltext |
| 856 | 4 | 0 | |u https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.110.225201 |x Verlag |z lizenzpflichtig |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20221025 | ||
| 993 | |a Article | ||
| 994 | |a 2011 | ||
| 998 | |g 124606431 |a Most, Patrick |m 124606431:Most, Patrick |d 910000 |d 910100 |e 910000PM124606431 |e 910100PM124606431 |k 0/910000/ |k 1/910000/910100/ |p 17 |y j | ||
| 998 | |g 108916618 |a Katus, Hugo |m 108916618:Katus, Hugo |d 910000 |d 910100 |e 910000PK108916618 |e 910100PK108916618 |k 0/910000/ |k 1/910000/910100/ |p 13 | ||
| 998 | |g 130878588 |a Hippe, Hans-Jörg |m 130878588:Hippe, Hans-Jörg |d 910000 |d 910100 |e 910000PH130878588 |e 910100PH130878588 |k 0/910000/ |k 1/910000/910100/ |p 11 | ||
| 998 | |g 121693449 |a Müller, Oliver J. |m 121693449:Müller, Oliver J. |d 910000 |d 910100 |e 910000PM121693449 |e 910100PM121693449 |k 0/910000/ |k 1/910000/910100/ |p 8 | ||
| 998 | |g 133026442 |a Völkers, Mirko |m 133026442:Völkers, Mirko |d 910000 |d 910100 |e 910000PV133026442 |e 910100PV133026442 |k 0/910000/ |k 1/910000/910100/ |p 1 |x j | ||
| 999 | |a KXP-PPN1819880524 |e 4201661261 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"relHost":[{"recId":"266880126","disp":"The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through Gβγ-mediated L-type calcium current disinhibitionCirculation research","language":["eng"],"type":{"media":"Online-Ressource","bibl":"periodical"},"pubHistory":["1.1953 -"],"corporate":[{"role":"isb","display":"American Heart Association"}],"origin":[{"publisher":"Assoc.","dateIssuedDisp":"1953-","dateIssuedKey":"1953","publisherPlace":"New York, NY"}],"title":[{"title":"Circulation research","title_sort":"Circulation research","subtitle":"an official journal of the American Heart Association"}],"physDesc":[{"extent":"Online-Ressource"}],"part":{"volume":"108","text":"108(2011), 1 vom: 7. Jan., Seite 27-39","pages":"27-39","year":"2011","issue":"1","extent":"13"},"id":{"eki":["266880126"],"zdb":["1467838-X"],"issn":["1524-4571"]},"note":["Gesehen am 09.08.2019"]}],"note":["Ursprünglich veröffentlicht Version 1: 24 Nov 2010","Im Text ist \"βγ\" tiefgestellt","Gesehen am 25.10.2022"],"physDesc":[{"extent":"13 S."}],"type":{"bibl":"article-journal","media":"Online-Ressource"},"id":{"eki":["1819880524"],"doi":["10.1161/CIRCRESAHA.110.225201"]},"language":["eng"],"title":[{"title_sort":"inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through Gβγ-mediated L-type calcium current disinhibition","title":"The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through Gβγ-mediated L-type calcium current disinhibition"}],"titleAlt":[{"title":"The inotropic peptide beta ARKct improves beta AR responsiveness in normal and failing cardiomyocytes through G beta upsilon -mediated L-type calcium current disinhibition"},{"title":"The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through G βγ-mediated L-type calcium current disinhibition"}],"person":[{"role":"aut","family":"Völkers","given":"Mirko","display":"Völkers, Mirko"},{"role":"aut","family":"Weidenhammer","given":"Christian","display":"Weidenhammer, Christian"},{"role":"aut","family":"Herzog","given":"Nicole","display":"Herzog, Nicole"},{"role":"aut","family":"Qiu","display":"Qiu, Gang","given":"Gang"},{"display":"Spaich, Kristin","given":"Kristin","family":"Spaich","role":"aut"},{"family":"von Wegner","display":"von Wegner, Frederic","given":"Frederic","role":"aut"},{"role":"aut","family":"Peppel","display":"Peppel, Karsten","given":"Karsten"},{"given":"Oliver J.","display":"Müller, Oliver J.","family":"Müller","role":"aut"},{"role":"aut","given":"Stefanie","display":"Schinkel, Stefanie","family":"Schinkel"},{"display":"Rabinowitz, Joseph E.","given":"Joseph E.","family":"Rabinowitz","role":"aut"},{"display":"Hippe, Hans-Jörg","given":"Hans-Jörg","family":"Hippe","role":"aut"},{"display":"Brinks, Henriette","given":"Henriette","family":"Brinks","role":"aut"},{"role":"aut","family":"Katus","display":"Katus, Hugo","given":"Hugo"},{"role":"aut","display":"Koch, Walter J.","given":"Walter J.","family":"Koch"},{"family":"Eckhart","given":"Andrea D.","display":"Eckhart, Andrea D.","role":"aut"},{"family":"Friedrich","display":"Friedrich, Oliver","given":"Oliver","role":"aut"},{"role":"aut","family":"Most","given":"Patrick","display":"Most, Patrick"}],"recId":"1819880524","origin":[{"dateIssuedKey":"2011","dateIssuedDisp":"2011"}],"name":{"displayForm":["Mirko Völkers, Christian Weidenhammer, Nicole Herzog, Gang Qiu, Kristin Spaich, Frederic von Wegner, Karsten Peppel, Oliver J. Müller, Stefanie Schinkel, Joseph E. Rabinowitz, Hans-Jörg Hippe, Henriette Brinks, Hugo A. Katus, Walter J. Koch, Andrea D. Eckhart, Oliver Friedrich, Patrick Most"]}} | ||
| SRT | |a VOELKERSMIINOTROPICP2011 | ||