Serotonin is a novel survival factor of cardiomyocytes: mitochondria as a target of 5‐HT<sub>2B</sub>‐receptor signaling

Nebigil, Canan G.; Étienne, Noémie; Messaddeq, Nadia; Maroteaux, Luc

doi:10.1096/fj.02-1122fje

Cited by 140 publications

(124 citation statements)

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“…The biological activity of PAMH suggests interesting possibilities for pharmacological modulation of muscle growth and function. In addition to influencing cardiac growth and development, 5-HT 2B receptor signaling promotes myocyte survival and mitochondrial biogenesis (33). Recent studies have also revealed a profound stimulatory effect of PAMH on skeletal muscle development (unpublished results).…”

Section: Discussionmentioning

confidence: 91%

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

Bush

Fielitz²,

Melvin

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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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. 2). Activation of the calcium, calmodulin-dependent phosphatase calcineurin, is sufficient and, in many cases, necessary for pathological cardiac hypertrophy (3), a major predictor of human morbidity and mortality (4). Thus, there has been intense interest in identifying novel small molecules capable of therapeutically modulating cardiac calcineurin signaling.Many calcineurin-sensitive genes are controlled by members of the nuclear factor of activated T-cell (NFAT) family of transcription factors, which translocate to the nucleus when dephosphorylated by calcineurin (reviewed in ref. 5). The calcineurin pathway also stimulates the myocyte enhancer factor-2 (MEF2) transcription factor by multiple mechanisms (6). We have shown that calcineurin activates a kinase that phosphorylates class II histone deacetylases (HDACs), which act as MEF2 corepressors (7). Signal-dependent phosphorylation of class II HDACs triggers their export from the nucleus and activation of MEF2 target genes (8, 9). HDAC mutants lacking the signalresponsive phosphorylation sites are refractory to calcium signaling and prevent cardiomyocyte hypertrophy. Conversely, mice lacking class II HDACs are hypersensitive to the growthpromoting activity of calcineurin (7).The activity of calcineurin is influenced by cofactors known as modulatory calcineurin-interacting proteins (MCIPs) or calcipressins (reviewed in ref. 10). Recent studies in yeast (11) and mammalian cells (12-14) have revealed both positive and negative roles for these proteins in the control of calcineurin activity. Overexpression of MCIP1 (also called Down syndrome critical region 1), for example, suppresses calcineurin signaling (12). In contrast, MCIP1 also seems to potentiate calcineurin signaling, as demonstrated by the diminution of calcineurin activity in the hearts of MCIP1 knockout mice (13). Intriguingly, the MCIP1 gene is a target of NFAT and is up-regulated in response to calcineurin signaling (15), which has been propo...

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Section: Discussionmentioning

confidence: 91%

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

Bush

Fielitz²,

Melvin

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…The second major result is that 5-HT 2B R could regulate numbers, morphology and function of central nervous work showing a protective function of 5-HT 2B R in newborn cardiomyocytes [50]. These studies will have to be extended to adult spinal cord microglia to determine the effect of aging, as well as the potential role of microglial location in their response to 5-HT 2B R stimulation.…”

Section: Discussionmentioning

confidence: 99%

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

et al. 2016

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Abstract:Microglia are the resident phagocytes of the central nervous system and have been implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). During neurodegeneration, microglial activation is accompanied by infiltration of circulating monocytes, leading to overall increased phagocytic activity and production of multiple inflammatory mediators in the spinal cord. Degenerative alterations in monocytes and microglia are commonly observed during neurodegenerative diseases, yet little is known concerning the mechanisms leading to their degeneration, or the consequences on disease progression. Here we observed that the serotonin 2B receptor (5-HT 2B ), a serotonin receptor expressed in microglia, is upregulated in the spinal cord of three different transgenic mouse models of ALS. In mutant SOD1 mice, this upregulation was restricted to cells positive for CD11b, a marker of mononuclear phagocytes. Ablation of 5-HT 2B receptor in transgenic ALS mice expressing mutant SOD1 resulted in increased degeneration of mononuclear phagocytes, as evidenced by fragmentation of Iba1-positive cellular processes. This was accompanied by decreased expression of key neuroinflammatory genes but also loss of expression of homeostatic microglial genes. Importantly, the dramatic effect of 5-HT 2B receptor ablation on mononuclear phagocytes was associated with acceleration of disease progression. To determine the translational relevance of these results, we studied polymorphisms in the human HTR2B gene, which encodes the 5-HT 2B receptor, in a large cohort of ALS patients. In this cohort, the C allele of SNP rs10199752 in HTR2B was associated with longer survival. Moreover, patients carrying one copy of the C allele of SNP rs10199752 showed increased 5-HT 2B mRNA in spinal cord and displayed less pronounced degeneration of mononuclear phagocytes than patients carrying two copies of the more common A allele. Thus functional 5-HT 2B receptors limit degeneration of spinal cord macrophages (most likely microglia), and slow disease progression in ALS. Targeting this receptor might be therapeutically useful.

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“…The 'trophic' activity of this neurotransmitter is also demonstrated in peripheral tissues, like in vascular smooth muscle cells (VSMC) where 5-HT remains a growth-modulating factor beyond the fetal period (Kawano et al, 2001). Recently, 5-HT has also been described as a survival factor of cardiomyocytes (Nebigil et al, 2003;Nebigil and Maroteaux, 2001).…”

Section: Discussionmentioning

confidence: 99%

Serotonin Depletion Hampers Survival and Proliferation in Neurospheres Derived from Adult Neural Stem Cells

Benninghoff¹,

Gritti²,

Rizzi³

et al. 2009

Neuropsychopharmacol

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Serotonin (5-HT) and the serotonergic system have recently been indicated as modulators of adult hippocampal neurogenesis. In this study, we evaluated the role of 5-HT on the functional features in neurospheres derived from adult neural stem cells (ANSC). We cultured neurospheres derived from mouse hippocampus in serum-free medium containing epidermal (EGF) and type-2 fibroblast growth factor (FGF2). Under these conditions ANSC expressed both isoforms of tryptophane-hydroxylase (TPH) and produced 5-HT. Blocking TPH function by para-chlorophenylalanine (PCPA) reduced ANSC proliferation, which was rescued by exogenous 5-HT. 5-HT action on ANSC was mediated predominantly by the serotonin receptor subtype 5-HT1A and, to a lesser extent, through the 5-HT2C (receptor) subtype, as shown by selectively antagonizing these receptors. Finally, we documented a 5-HT-induced increase of ANSC migration activity. In summary, we demonstrated a powerful serotonergic impact on ANSC functional features, which was mainly mediated by 5-HT1A receptors.

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Serotonin is a novel survival factor of cardiomyocytes: mitochondria as a target of 5‐HT_2B‐receptor signaling

Cited by 140 publications

References 58 publications

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

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

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

Serotonin Depletion Hampers Survival and Proliferation in Neurospheres Derived from Adult Neural Stem Cells

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Serotonin is a novel survival factor of cardiomyocytes: mitochondria as a target of 5‐HT2B‐receptor signaling

Cited by 140 publications

References 58 publications

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

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

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

Serotonin Depletion Hampers Survival and Proliferation in Neurospheres Derived from Adult Neural Stem Cells

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Serotonin is a novel survival factor of cardiomyocytes: mitochondria as a target of 5‐HT_2B‐receptor signaling