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Inhibition of Autophagy in Cardiomyocytes by Calmodulin Antagonists
Author(s) -
Lopez Vanessa,
Hayden Matt,
Giles Jennifer,
Keomanivong Faithe,
Wauson Eric M,
Tran QuangKim
Publication year - 2019
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.2019.33.1_supplement.lb397
Subject(s) - autophagy , trifluoperazine , bafilomycin , intracellular , calmodulin , microbiology and biotechnology , flux (metallurgy) , chloroquine , chemistry , basal (medicine) , biology , biochemistry , endocrinology , immunology , apoptosis , organic chemistry , malaria , insulin , enzyme
Macroautophagy (hereafter referred to as autophagy) is a catabolic process that regulates important aspects of myocardial metabolism. While numerous studies have indicated involvement of signaling via Ca 2+ in autophagic flux, the precise mechanisms remain unknown. Calmodulin (CaM) is a ubiquitous transducer of intracellular Ca 2+ signals by interacting with an estimated network of 300 cellular proteins. We have begun to examine the role of CaM in autophagic flux in cardiomyocytes. A basal level of autophagy is required for normal myocardial function. Chloroquine dose‐dependently reduces basal autophagic flux in H9c2 cardiomyocytes, as indicated by LC3 immunoblotting, p62 immunofluorescence, and autophagic flux assays. Competitive binding assays using purified CaM and FRET‐based CaM biosensors demonstrate direct Ca 2+ ‐dependent CaM binding to chloroquine. The structurally distinct CaM antagonists W‐7, trifluoperazine, and CGS 9343B also dose‐dependently inhibit basal autophagic flux by reducing autophagosome degradation. Most CaM‐dependent processes depend at the front end on the amplitude and dynamics of intracellular Ca 2+ signals. Interestingly, chloroquine, W‐7, trifluoperazine, and CGS 9343b all mobilize intracellular Ca 2+ . The effects of these pharmacological agents to inhibit autophagic flux are thus associated with their inhibition of CaM and not of initial Ca 2+ signals produced in cells. These data indicate a role for CaM in the control of autophagic flux in cardiomyocytes. Support or Funding Information American Heart Association (15SDG25090279) and Iowa Osteopathic Education and Research Funds (Eric Wauson); NIH HL112184 and DMU IOER‐090717 ( Quang‐Kim Tran) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .