51. Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish.
- Author
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Wythe JD, Jurynec MJ, Urness LD, Jones CA, Sabeh MK, Werdich AA, Sato M, Yost HJ, Grunwald DJ, Macrae CA, and Li DY
- Subjects
- 1-Phosphatidylinositol 4-Kinase metabolism, Animals, Body Patterning, Bradycardia embryology, Bradycardia physiopathology, Calcium Signaling, Cardiac Output, Cell Count, Embryo, Nonmammalian metabolism, Embryo, Nonmammalian pathology, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, HEK293 Cells, Heart embryology, Heart physiology, Humans, Muscle Proteins deficiency, Muscle Proteins genetics, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Organogenesis, Protein Binding, Protein Structure, Tertiary, Subcellular Fractions metabolism, Zebrafish embryology, Zebrafish genetics, Zebrafish Proteins deficiency, Zebrafish Proteins genetics, Muscle Proteins chemistry, Muscle Proteins metabolism, Myocardial Contraction physiology, Zebrafish metabolism, Zebrafish Proteins chemistry, Zebrafish Proteins metabolism
- Abstract
The vertebrate heart is one of the first organs to form, and its early function and morphogenesis are crucial for continued embryonic development. Here we analyze the effects of loss of Heart adaptor protein 1 (Hadp1), which we show is required for normal function and morphogenesis of the embryonic zebrafish heart. Hadp1 is a pleckstrin homology (PH)-domain-containing protein whose expression is enriched in embryonic cardiomyocytes. Knockdown of hadp1 in zebrafish embryos reduced cardiac contractility and altered late myocyte differentiation. By using optical mapping and submaximal levels of hadp1 knockdown, we observed profound effects on Ca(2+) handling and on action potential duration in the absence of morphological defects, suggesting that Hadp1 plays a major role in the regulation of intracellular Ca(2+) handling in the heart. Hadp1 interacts with phosphatidylinositol 4-phosphate [PI4P; also known as PtdIns(4)P] derivatives via its PH domain, and its subcellular localization is dependent upon this motif. Pharmacological blockade of the synthesis of PI4P derivatives in vivo phenocopied the loss of hadp1 in zebrafish. Collectively, these results demonstrate that hadp1 is required for normal cardiac function and morphogenesis during embryogenesis, and suggest that hadp1 modulates Ca(2+) handling in the heart through its interaction with phosphatidylinositols.
- Published
- 2011
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