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The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through G(βγ)-mediated L-type calcium current disinhibition.

Völkers M, Weidenhammer C, Herzog N, Qiu G, Spaich K, von Wegner F, Peppel K, Müller OJ, Schinkel S, Rabinowitz JE, Hippe HJ, Brinks H, Katus H, Koch WJ, Eckhart AD, Friedrich O, Most P (2011)

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Publication Language: English

Publication Status: Published

Publication Type: Journal article, Original article

Publication year: 2011

Journal

Book Volume: 108

Pages Range: 27-39

Journal Issue: 1

URI: http://circres.ahajournals.org/content/108/1/27

DOI: 10.1161/CIRCRESAHA.110.225201

Open Access Link: http://circres.ahajournals.org/content/108/1/27.full.pdf+html

Abstract

RATIONALE\nThe G(βγ)-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 G(βγ)-mediated signaling have yet to be fully elucidated.\nOBJECTIVE\nWe sought to identify G(βγ)-regulated targets and signaling mechanisms conveying βARKct-mediated enhanced βAR responsiveness in normal (NC) and failing (FC) adult rat ventricular cardiomyocytes.\nMETHODS AND RESULTS\nAssessing 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 (I(Ca)) both in NCs and FCs on βAR stimulation. Mechanistically, βARKct augments I(Ca) by preventing enhanced inhibitory interaction between the α1-LCC subunit (Cav1.2α) and liberated G(βγ) 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 I(Ca) and Ca²(+) transients, being susceptible to suppression by recombinant G(βγ) 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.\nCONCLUSION\nOur study identifies a G(βγ)-dependent signaling pathway attenuating cardiomyocyte I(Ca) on βAR as molecular target for the G(βγ)-sequestering peptide βARKct. Targeted interruption of this inhibitory signaling pathway by βARKct confers improved βAR contractile responsiveness through increased I(Ca) without enhancing regular or restoring abnormal cAMP-signaling. βARKct-mediated improvement of I(Ca) rendered cardiomyocytes neither susceptible to βAR-induced damage nor arrhythmogenic sarcoplasmic reticulum Ca²(+) leakage.

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APA:

Völkers, M., Weidenhammer, C., Herzog, N., Qiu, G., Spaich, K., von Wegner, F.,... Most, P. (2011). The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through G(βγ)-mediated L-type calcium current disinhibition. Circulation Research, 108(1), 27-39. https://doi.org/10.1161/CIRCRESAHA.110.225201

MLA:

Völkers, Mirko, et al. "The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through G(βγ)-mediated L-type calcium current disinhibition." Circulation Research 108.1 (2011): 27-39.

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