TY - JOUR
T1 - Constitutive BDNF/TrkB signaling is required for normal cardiac contraction and relaxation
AU - Feng, Ning
AU - Huke, Sabine
AU - Zhua, Guangshuo
AU - Tocchetti, Carlo G.
AU - Shi, Sa
AU - Aiba, Takeshi
AU - Kaludercice, Nina
AU - Hooverf, Donald B.
AU - Beckg, Sarah E.
AU - Mankowskig, Joseph L.
AU - Tomaselli, Gordon F.
AU - Bersh, Donald M.
AU - Kassa, David A.
AU - Paoloccia, Nazareno
PY - 2015/2/10
Y1 - 2015/2/10
N2 - BDNF and its associated tropomyosin-related kinase receptor B (TrkB) nurture vessels and nerves serving the heart. However, the direct effect of BDNF/TrkB signaling on the myocardium is poorly understood. Here we report that cardiac-specific TrkB knockout mice (TrkB-/-) display impaired cardiac contraction and relaxation, showing that BDNF/TrkB signaling acts constitutively to sustain in vivo myocardial performance. BDNF enhances normal cardiomyocyte Ca2+ cycling, contractility, and relaxation via Ca2+/calmodulindependent protein kinase II (CaMKII). Conversely, failing myocytes, which have increased truncated TrkB lacking tyrosine kinase activity and chronically activated CaMKII, are insensitive to BDNF. Thus, BDNF/TrkB signaling represents a previously unidentified pathway by which the peripheral nervous system directly and tonically influences myocardial function in parallel with β-adrenergic control. Deficits in this system are likely additional contributors to acute and chronic cardiac dysfunction. BDNF TrkB receptorcardiac contractility/relaxation CaMKII neurotrophins We are grateful to Dr. David D. Ginty for providing us with TrkBF616A and TrkB conditional knockout mice.
AB - BDNF and its associated tropomyosin-related kinase receptor B (TrkB) nurture vessels and nerves serving the heart. However, the direct effect of BDNF/TrkB signaling on the myocardium is poorly understood. Here we report that cardiac-specific TrkB knockout mice (TrkB-/-) display impaired cardiac contraction and relaxation, showing that BDNF/TrkB signaling acts constitutively to sustain in vivo myocardial performance. BDNF enhances normal cardiomyocyte Ca2+ cycling, contractility, and relaxation via Ca2+/calmodulindependent protein kinase II (CaMKII). Conversely, failing myocytes, which have increased truncated TrkB lacking tyrosine kinase activity and chronically activated CaMKII, are insensitive to BDNF. Thus, BDNF/TrkB signaling represents a previously unidentified pathway by which the peripheral nervous system directly and tonically influences myocardial function in parallel with β-adrenergic control. Deficits in this system are likely additional contributors to acute and chronic cardiac dysfunction. BDNF TrkB receptorcardiac contractility/relaxation CaMKII neurotrophins We are grateful to Dr. David D. Ginty for providing us with TrkBF616A and TrkB conditional knockout mice.
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U2 - 10.1073/pnas.1417949112
DO - 10.1073/pnas.1417949112
M3 - Article
C2 - 25583515
AN - SCOPUS:84922665700
SN - 0027-8424
VL - 112
SP - 1880
EP - 1885
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 6
ER -