title: Constitutive BDNF/TrkB signaling is required for normal cardiac contraction and relaxation.
abstract: 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 Ca(2+) cycling, contractility, and relaxation via Ca(2+)/calmodulin-dependent 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.
authors.affiliation: Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205;
authors.forename: Ning
authors.initials: N
authors.lastname: Feng
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Sabine
authors.initials: S
authors.lastname: Huke
authors.affiliation: Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205;
authors.forename: Guangshuo
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Clinica Montevergine, 83013 Mercogliano, Italy;
authors.forename: Carlo G
authors.initials: CG
authors.lastname: Tocchetti
authors.affiliation: Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205;
authors.forename: Sa
authors.initials: S
authors.lastname: Shi
authors.affiliation: Division of Arrhythmia and Electrophysiology, National Cerebral and Cardiovascular Center, Osaka 565-8565, Japan;
authors.forename: Takeshi
authors.initials: T
authors.lastname: Aiba
authors.affiliation: Neuroscience Institute, National Research Council of Italy, 35131 Padova, Italy;
authors.forename: Nina
authors.initials: N
authors.lastname: Kaludercic
authors.affiliation: Department of Biomedical Science, East Tennessee State University, Johnson City, TN 37614;
authors.forename: Donald B
authors.initials: DB
authors.lastname: Hoover
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205;
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Beck
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205;
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Mankowski
authors.affiliation: Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205;
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Tomaselli
authors.affiliation: Department of Pharmacology, University of California, Davis, CA 95616; and.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.affiliation: Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205;
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.affiliation: Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205; Dipartimento di Medicina Clinica e Sperimentale, Universita' di Perugia, 06132 Perugia, Italy npaoloc1@jhmi.edu.
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D003971:Diastole / Q000502:physiology*; D006439:Hemodynamics; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology*; D018408:Patch-Clamp Techniques; D020813:Receptor, trkB / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB; D002118:Calcium
keywords: BDNF; CaMKII; TrkB receptor; cardiac contractility/relaxation; neurotrophins