Pepducin ICL1-9-Mediated β2-Adrenergic Receptor-Dependent Cardiomyocyte Contractility Occurs in a $ G_{i} $ Protein/ROCK/PKD-Sensitive Manner
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 $ G_{s} $ 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 $ G_{i} $ 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 $ G_{i} $ protein/βarr-dependent activation of RhoA/ROCK/PKD signaling..
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:37 |
|---|---|
| Enthalten in: |
Cardiovascular drugs and therapy - 37(2022), 2 vom: 08. Jan., Seite 245-256 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Okyere, Ama Dedo [VerfasserIn] |
|---|
| Links: |
Volltext [lizenzpflichtig] |
|---|
| Themen: |
β2-Adrenergic receptor |
|---|
| Anmerkungen: |
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021 |
|---|
| doi: |
10.1007/s10557-021-07299-4 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
SPR049591339 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | SPR049591339 | ||
| 003 | DE-627 | ||
| 005 | 20230323103923.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 230323s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s10557-021-07299-4 |2 doi | |
| 035 | |a (DE-627)SPR049591339 | ||
| 035 | |a (SPR)s10557-021-07299-4-e | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Okyere, Ama Dedo |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Pepducin ICL1-9-Mediated β2-Adrenergic Receptor-Dependent Cardiomyocyte Contractility Occurs in a $ G_{i} $ Protein/ROCK/PKD-Sensitive Manner |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021 | ||
| 520 | |a 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 $ G_{s} $ 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 $ G_{i} $ 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 $ G_{i} $ protein/βarr-dependent activation of RhoA/ROCK/PKD signaling. | ||
| 650 | 4 | |a β2-Adrenergic receptor |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Rho-associated protein kinase |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a G protein |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Pepducin |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Song, Jianliang |4 aut | |
| 700 | 1 | |a Patwa, Viren |4 aut | |
| 700 | 1 | |a Carter, Rhonda L. |4 aut | |
| 700 | 1 | |a Enjamuri, Nitya |4 aut | |
| 700 | 1 | |a Lucchese, Anna Maria |4 aut | |
| 700 | 1 | |a Ibetti, Jessica |4 aut | |
| 700 | 1 | |a de Lucia, Claudio |4 aut | |
| 700 | 1 | |a Schumacher, Sarah M. |4 aut | |
| 700 | 1 | |a Koch, Walter J. |4 aut | |
| 700 | 1 | |a Cheung, Joseph Y. |4 aut | |
| 700 | 1 | |a Benovic, Jeffrey L. |4 aut | |
| 700 | 1 | |a Tilley, Douglas G. |0 (orcid)0000-0002-9681-3377 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cardiovascular drugs and therapy |d Dordrecht [u.a.] : Springer Science + Business Media B.V, 1987 |g 37(2022), 2 vom: 08. Jan., Seite 245-256 |w (DE-627)SPR011281340 |w (DE-600)2003553-6 |x 1573-7241 |7 nnns |
| 773 | 1 | 8 | |g volume:37 |g year:2022 |g number:2 |g day:08 |g month:01 |g pages:245-256 |
| 856 | 4 | 0 | |u https://dx.doi.org/10.1007/s10557-021-07299-4 |z lizenzpflichtig |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_SPRINGER | ||
| 951 | |a AR | ||
| 952 | |d 37 |j 2022 |e 2 |b 08 |c 01 |h 245-256 | ||