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Phospholipase C ε Regulates Multiple Agonists‐Induced Cardiomyocyte Hypertrophy in Neonatal Rat Ventricular Myocytes By Binding To mAKAP (Muscle A‐Kinase Anchoring Protein) And Generating Local IP3‐Dependent Nuclear Calcium Release
Author(s) -
Zhang Lianghui,
Malik Sundeep,
Park Keigan M,
Kapiloff Michael S,
Yule David I,
Smrcka Alan V
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1012.1
Subject(s) - microbiology and biotechnology , myocyte , phospholipase c , biology , muscle hypertrophy , medicine , signal transduction , endocrinology
Phospholipase Cε (PLCε) is a bifunctional PLC isoform that contains a PLC catalytic, Ras association (RA), and guanine nucleotide exchange factor (GEF) domains. To determine if PLCε plays a direct role in regulating cardiomyocyte hypertrophy, neonatal rat ventricular myocytes (NRVMs) were infected with adenoviruses expressing PLCε siRNA. PLCε siRNA infection of NRVMs inhibits Endothelin‐1 (ET‐1), isoproterenol (ISO) and insulin like growth factor‐1 (IGF‐1) induced protein synthesis and ANF ( Atrial natriuretic peptide) mRNA expression – indexes of cardiac hypertrophy. These data indicate that PLCε signaling downstream of ET‐1R, βAR and IGFR is important for cardiac hypertrophy. PLCε bound to mAKAP (muscle A‐kinase anchoring protein), which localizes bound proteins to the nuclear envelope of myocytes. Overexpression of PLCε‐RA1 domain disrupts PLCε binding to mAKAP. Overexpression of the PLCε‐RA1 domain in NRVMs significantly reduces ET‐1, ISO and IGF‐1‐induced hypertrophy. To examine the role of PLCε and PLCε‐mAKAP scaffolding at the nuclear envelope, we measure nuclear Ca 2+ release. PLCε siRNA and PLCε‐RA1 domain overexpression reduce ET‐1‐induced nuclear Ca 2+ release in NRVMs. These results suggest that PLCε, scaffolded at the nuclear envelope, responds to multiple upstream signals to regulate cardiomyocyte hypertrophy via IP 3 ‐ dependent nuclear Ca 2+ release.