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

Item Type:	Article
Title:	A small molecular activator of cardiac hypertrophy uncovered in a chemical screen for modifiers of the calcineurin signaling pathway
Creators Name:	Bush, E. and Fielitz, J. and Melvin, L. and Martinez-Arnold, M. and McKinsey, T.A. and Plichta, R. and Olson, E.N.
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-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.
Keywords:	Biological Models, Calcineurin, Cardiomegaly, Cell Line, Cultured Cells, Gene Expression Regulation, Genetic Transcription, Heart, Intracellular Signaling Peptides and Proteins, Muscle Proteins, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, Serotonin, Signal Transduction, Transfection, Animals, Newborn Animals, Rats
Source:	Proceedings of the National Academy of Sciences of the United States of America
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Volume:	101
Number:	9
Page Range:	2870-2875
Date:	2 March 2004
Official Publication:	https://doi.org/10.1073/pnas.0308723101
PubMed:	View item in PubMed

Repository Staff Only: item control page