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- Title
Pepducin ICL1-9-Mediated β2-Adrenergic Receptor-Dependent Cardiomyocyte Contractility Occurs in a G<sub>i</sub> Protein/ROCK/PKD-Sensitive Manner.
- Authors
Okyere, Ama Dedo; Song, Jianliang; Patwa, Viren; Carter, Rhonda L.; Enjamuri, Nitya; Lucchese, Anna Maria; Ibetti, Jessica; de Lucia, Claudio; Schumacher, Sarah M.; Koch, Walter J.; Cheung, Joseph Y.; Benovic, Jeffrey L.; Tilley, Douglas G.
- Abstract
Purpose: β-Adrenergic receptors (βAR) are essential targets for the treatment of heart failure (HF); however, chronic use of βAR agonists as positive inotropes to increase contractility in a Gs protein-dependent manner is associated with increased mortality. Alternatively, we previously reported that allosteric modulation of β2AR with the pepducin intracellular loop (ICL)1-9 increased cardiomyocyte contractility in a β-arrestin (βarr)-dependent manner, and subsequently showed that ICL1-9 activates the Ras homolog family member A (RhoA). Here, we aimed to elucidate both the proximal and downstream signaling mediators involved in the promotion of cardiomyocyte contractility in response to ICL1-9. Methods: We measured adult mouse cardiomyocyte contractility in response to ICL1-9 or isoproterenol (ISO, as a positive control) alone or in the presence of inhibitors of various potential components of βarr- or RhoA-dependent signaling. We also assessed the contractile effects of ICL1-9 on cardiomyocytes lacking G protein-coupled receptor (GPCR) kinase 2 (GRK2) or 5 (GRK5). Results: Consistent with RhoA activation by ICL1-9, both Rho-associated protein kinase (ROCK) and protein kinase D (PKD) inhibition were able to attenuate ICL1-9-mediated contractility, as was inhibition of myosin light chain kinase (MLCK). While neither GRK2 nor GRK5 deletion impacted ICL1-9-mediated contractility, pertussis toxin attenuated the response, suggesting that ICL1-9 promotes downstream RhoA-dependent signaling in a Gi protein-dependent manner. Conclusion: Altogether, our study highlights a novel signaling modality that may offer a new approach to the promotion, or preservation, of cardiac contractility during HF via the allosteric regulation of β2AR to promote Gi protein/βarr-dependent activation of RhoA/ROCK/PKD signaling.
- Subjects
MYOSIN light chain kinase; RHO-associated kinases; PROTEIN kinases; G protein coupled receptors; PERTUSSIS toxin; ALDOSTERONE antagonists; CONTRACTILE proteins
- Publication
Cardiovascular Drugs & Therapy, 2023, Vol 37, Issue 2, p245
- ISSN
0920-3206
- Publication type
Article
- DOI
10.1007/s10557-021-07299-4