Sarah Schumacher-Bass, PhD
Lerner Research Institute,
9500 Euclid Avenue, Cleveland, Ohio 44195
While significant advances have been made in stabilizing and relieving patient symptoms, the underlying mechanisms of cardiac remodeling and decompensation to heart failure remain a major focus of research efforts towards therapeutic development. One signaling mechanism that plays a critical role in regulating cardiac function is that of G protein-coupled receptors (GPCRs), a large family of diverse membrane receptors that is tightly controlled by GPCR kinases (GRKs), such as GRK2 (βARK1). In addition to its well-characterized role in the regulation of GPCRs, ongoing research has demonstrated great diversity in the functional roles of GRK2. The mechanisms by which these functions occur in vivo are poorly understood, perhaps due to our limited understanding of the distinct domains of GRK2 and the protein interactions they encompass. In order to study functional interactions in the amino terminus of GRK2, we generated transgenic mice with cardiomyocyte-restricted expression of peptide fragments of this enzyme, and found that both the Regulator of G-protein Signaling (RGS) domain of GRK2 (βARKrgs) and a shorter N-terminal peptide (βARKnt) can alter cardiac physiology when expressed in myocytes. Of note, both peptides halt heart failure progression in a mouse model of pressure-overload but have divergent effects on the initial hypertrophic response. This is in contrast to the gain or loss of function of the full-length enzyme that does not alter cardiac hypertrophy, and occurs through distinct, kinase-independent protein-binding interactions embodied by the βARKrgs and βARKnt peptides, that do not occur for full-length GRK2 in vivo. Therefore, βARKrgs and βARKnt, compared to GRK2, will serve as tools to investigate protein interactions involved in normal, adaptive, and maladaptive cardiovascular remodeling. We use a combination of cell culture, pharmacology, proteomics, histology, structure-based drug design, and transgenic mouse models to elucidate the mechanisms that underlie the transition from adaptive to adverse remodeling, including changes in cardiac structure, function, metabolism, fibrosis, and arrhythmogenesis in various models of human disease.
- Schumacher SM, Koch WJ. Noncanonical Roles of G Protein-coupled Receptor Kinases in Cardiovascular Signaling. J Cardiovasc Pharmacol. 2017 Sep;70(3):129-141. doi: 10.1097/FJC.0000000000000483. PubMed PMID: 28328744; PubMed Central PMCID: PMC5591054.
- Schumacher SM. The Challenge of Mentorship. Circ Res. 2017 Apr 14;120(8):1232-1233. doi: 10.1161/CIRCRESAHA.117.310930. PubMed PMID: 28408449; PubMed Central PMCID: PMC5407462.
- Schumacher SM, Gao E, Cohen M, Lieu M, Chuprun JK, Koch WJ. A peptide of the RGS domain of GRK2 binds and inhibits Gα(q) to suppress pathological cardiac hypertrophy and dysfunction. Sci Signal. 2016 Mar 22;9(420):ra30. doi: 10.1126/scisignal.aae0549. PubMed PMID: 27016525; PubMed Central PMCID: PMC5015886.
- Makarewich CA, Troupes CD, Schumacher SM, Gross P, Koch WJ, Crandall DL, Houser SR. Comparative effects of urocortins and stresscopin on cardiac myocyte contractility. J Mol Cell Cardiol. 2015 Sep;86:179-86. doi: 10.1016/j.yjmcc.2015.07.023. Epub 2015 Jul 29. PubMed PMID: 26231084; PubMed Central PMCID: PMC4558371.
- Schumacher SM, Gao E, Zhu W, Chen X, Chuprun JK, Feldman AM, Tesmer JJ, Koch WJ. Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction. Sci Transl Med. 2015 Mar 4;7(277):277ra31. doi: 10.1126/scitranslmed.aaa0154. PubMed PMID: 25739765; PubMed Central PMCID: PMC4768806.
- Schumacher-Bass SM, Vesely ED, Zhang L, Ryland KE, McEwen DP, Chan PJ, Frasier CR, McIntyre JC, Shaw RM, Martens JR. Role for myosin-V motor proteins in the selective delivery of Kv channel isoforms to the membrane surface of cardiac myocytes.Circ Res. 2014 Mar 14;114(6):982-92. doi: 10.1161/CIRCRESAHA.114.302711. Epub 2014 Feb 7. PubMed PMID: 24508725; PubMed Central PMCID: PMC4213814.
- Milstein ML, Musa H, Balbuena DP, Anumonwo JM, Auerbach DS, Furspan PB, Hou L, Hu B, Schumacher SM, Vaidyanathan R, Martens JR, Jalife J. Dynamic reciprocity of sodium and potassium channel expression in a macromolecular complex controls cardiac excitability and arrhythmia. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):E2134-43. doi: 10.1073/pnas.1109370109. Epub 2012 Apr 16. PubMed PMID: 22509027; PubMed Central PMCID: PMC3412015.
- Schumacher SM, McEwen DP, Zhang L, Arendt KL, Van Genderen KM, Martens JR. Antiarrhythmic drug-induced internalization of the atrial-specific k+ channel kv1.5. Circ Res. 2009 Jun 19;104(12):1390-8. doi: 10.1161/CIRCRESAHA.108.192773. Epub 2009 May 14. PubMed PMID: 19443837; PubMed Central PMCID: PMC2731974.
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