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Media type:
E-Article
Title:
A small molecular activator of cardiac hypertrophy uncovered in a chemical screen for modifiers of the calcineurin signaling pathway
Contributor:
Bush, Erik;
Fielitz, Jens;
Melvin, Lawrence;
Martinez-Arnold, Michael;
McKinsey, Timothy A.;
Plichta, Ryan;
Olson, Eric N.
Published:
Proceedings of the National Academy of Sciences, 2004
Published in:
Proceedings of the National Academy of Sciences, 101 (2004) 9, Seite 2870-2875
Language:
English
DOI:
10.1073/pnas.0308723101
ISSN:
0027-8424;
1091-6490
Origination:
Footnote:
Description:
The calcium, calmodulin-dependent phosphatase calcineurin, regulates growth and gene expression of striated muscles. The activity of calcineurin is modulated by a family of cofactors, referred to as modulatory calcineurin-interacting proteins (MCIPs). In the heart, the MCIP1 gene is activated by calcineurin and has been proposed to fulfill a negative feedback loop that restrains potentially pathological calcineurin signaling, which would otherwise lead to abnormal cardiac growth. In a high-throughput screen for small molecules capable of regulating MCIP1 expression in muscle cells, we identified a unique 4-aminopyridine derivative exhibiting an embedded partial structural motif of serotonin (5-hydroxytryptamine, 5-HT). This molecule, referred to as pyridine activator of myocyte hypertrophy, acts as a selective agonist for 5-HT 2A/2B receptors and induces hypertrophy of cardiac muscle cells through a signaling pathway involving calcineurin and a kinase-dependent mechanism that inactivates class II histone deacetylases, which act as repressors of cardiac growth. These findings identify MCIP1 as a downstream target of 5-HT 2A/2B receptor signaling in cardiac muscle cells and suggest possible uses for 5-HT 2A/2B agonists and antagonists as modulators of cardiac growth and gene expression.