A small molecular activator of cardiac hypertrophy uncovered in a chemical screen for modifiers of the calcineurin signaling pathway

Erik Bush, Jens Fielitz, Lawrence Melvin, Michael Martinez-Arnold, Timothy A. McKinsey, Ryan Plichta, Eric N. Olson

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

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-HT2A/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-HT2A/2B receptor signaling in cardiac muscle cells and suggest possible uses for 5-HT2A/2B agonists and antagonists as modulators of cardiac growth and gene expression.

Original languageEnglish (US)
Pages (from-to)2870-2875
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number9
DOIs
StatePublished - Mar 2 2004

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Calcineurin
Cardiomegaly
Receptor, Serotonin, 5-HT2A
Growth
Cardiac Myocytes
Muscle Cells
Hypertrophy
Serotonin
Serotonin 5-HT2 Receptor Agonists
Serotonin 5-HT2 Receptor Antagonists
Gene Expression
4-Aminopyridine
Histone Deacetylases
Striated Muscle
Calmodulin
Phosphotransferases
Calcium
Genes
Proteins

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

A small molecular activator of cardiac hypertrophy uncovered in a chemical screen for modifiers of the calcineurin signaling pathway. / Bush, Erik; Fielitz, Jens; Melvin, Lawrence; Martinez-Arnold, Michael; McKinsey, Timothy A.; Plichta, Ryan; Olson, Eric N.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 9, 02.03.2004, p. 2870-2875.

Research output: Contribution to journalArticle

Bush, Erik ; Fielitz, Jens ; Melvin, Lawrence ; Martinez-Arnold, Michael ; McKinsey, Timothy A. ; Plichta, Ryan ; Olson, Eric N. / A small molecular activator of cardiac hypertrophy uncovered in a chemical screen for modifiers of the calcineurin signaling pathway. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 9. pp. 2870-2875.
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