title: Overlapping and opposing functions of G protein-coupled receptor kinase 2 (GRK2) and GRK5 during heart development.
abstract: G protein-coupled receptor kinases 2 (GRK2) and 5 (GRK5) are fundamental regulators of cardiac performance in adults but are less well characterized for their function in the hearts of embryos. GRK2 and -5 belong to different subfamilies and function as competitors in the control of certain receptors and signaling pathways. In this study, we used zebrafish to investigate whether the fish homologs of GRK2 and -5, Grk2/3 and Grk5, also have unique, complementary, or competitive roles during heart development. We found that they differentially regulate the heart rate of early embryos and equally facilitate heart function in older embryos and that both are required to develop proper cardiac morphology. A loss of Grk2/3 results in dilated atria and hypoplastic ventricles, and the hearts of embryos depleted in Grk5 present with a generalized atrophy. This Grk5 morphant phenotype was associated with an overall decrease of early cardiac progenitors as well as a reduction in the area occupied by myocardial progenitor cells. In the case of Grk2/3, the progenitor decrease was confined to a subset of precursor cells with a committed ventricular fate. We attempted to rescue the GRK loss-of-function heart phenotypes by downstream activation of Hedgehog signaling. The Grk2/3 loss-of-function embryos were rescued by this approach, but Grk5 embryos failed to respond. In summary, we found that GRK2 and GRK5 control cardiac function as well as morphogenesis during development although with different morphological outcomes.
authors.affiliation: Institute of Biochemistry and Molecular Biology and Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany. Electronic address: melanie.philipp@uni-ulm.de.
authors.forename: Melanie
authors.initials: M
authors.lastname: Philipp
authors.affiliation: Department of Internal Medicine II-Cardiology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany and.
authors.forename: Ina M
authors.initials: IM
authors.lastname: Berger
authors.affiliation: Department of Internal Medicine II-Cardiology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany and.
authors.forename: Steffen
authors.initials: S
authors.lastname: Just
authors.affiliation: Departments of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710; Departments of Medicine, and Duke University Medical Center, Durham, North Carolina 27710; Departments of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000502:physiology; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000502:physiology*; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006321:Heart / Q000196:embryology* / Q000254:growth & development; D006339:Heart Rate; D053823:Hedgehog Proteins / Q000378:metabolism; D060172:Morpholinos / Q000235:genetics; D009200:Myocardial Contraction; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D018919:Neovascularization, Physiologic; D009929:Organ Size; D038081:Organogenesis; D015398:Signal Transduction; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000502:physiology*
chemical_list: D053823:Hedgehog Proteins; D060172:Morpholinos; D029961:Zebrafish Proteins; D054769:G-Protein-Coupled Receptor Kinase 2; D054774:G-Protein-Coupled Receptor Kinase 5
keywords: Cardiac Development; Cardiovascular; Cell Signaling; G Protein-coupled Receptor Kinase; Heart Development; Hedgehog Signaling Pathway; Zebrafish
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