How serotonin receptors regulate morphogenic signalling in neurons

doi:10.1016/j.pneurobio.2016.03.007

Progress in Neurobiology

Volume 151, April 2017, Pages 35-56

https://doi.org/10.1016/j.pneurobio.2016.03.007 Get rights and content

Highlights

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Serotonin (5-HT) is critically involved in the regulation of multiple physiological and pathophysiological functions in the CNS.
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5-HT operates via a heterogenic receptor family comprising fourteen different receptors in mammals.
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5-HT is involved in neural development, neurite outgrowth, somatic morphology, growth cone motility, synapto- and spinogenesis.
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Evidences raise pivotal roles of 5-HT-mediated morphogenic signalling in mental disorders and neurodegenerative diseases (each bullet point starts in bold writing).

Abstract

Serotonin (5-hydroxytrympamine or 5-HT) is one of the phylogenetically oldest neurotransmitters, and the serotonergic system is among the earliest developed neuronal systems. Serotonin is critically involved in regulating multiple physiological functions, acting via a heterogenic receptor family that includes G protein-coupled receptors and ligand-gated ion channels. Although serotonergic neurons comprise a widely distributed and complex network that targets nearly every brain structure, serotonin-mediated signalling is under strict temporal and spatial control. Imbalance in serotonergic signalling is implicated in many pathophysiological conditions, including schizophrenia, Alzheimer’s disease, depression, and anxiety. In addition to its well-established role as a neurotransmitter, serotonin is involved in many aspects of neural development, including neurite outgrowth, somatic morphology regulation, growth cone motility, synaptogenesis, and control of dendritic spine shape and density. The morphogenic effects of serotonin are developmentally regulated, and serotonin availability during sensitive developmental stages can modulate the formation and functions of behaviourally relevant neuronal networks in adulthood. Here we provide an overview of the molecular mechanisms responsible for the morphogenic effects of serotonin elicited by its different receptors in neurons. We also discuss the role of serotonin receptor-mediated morphogenic signalling in the development and maintenance of pathophysiological conditions.

Section snippets

Discovery of serotonin and its receptors

The biogenic monoamine 5-hydroxytryptime (5-HT) acts as a tissue hormone, mitogen, neurotransmitter and neuromodulator (Fidalgo et al., 2013, Ramakrishna et al., 2011). In 1937, the Italian physiologist Vittorio Erspamer described a substance that he called enteramine, which was present in extracts isolated from gastric mucosa and enterochromaffin cells and which induced smooth muscle contraction in the rat and mouse gut (Vialli and Erspamer, 1937). Later, in 1948, Maurice Rapport of Irvine

Morphogenic signalling by defined 5-HT receptors

We presently lack a complete understanding of the molecular downstream mechanisms underlying the various and sometimes opposite effects of 5-HT on neuronal morphology. However, the high variability of reported effects suggests that the different morphogenic actions of 5-HT may be defined by the variable expressions of different 5-HT receptor subtypes and/or their downstream effectors in different brain areas. First experimental evidence for this concept was raised recently by demonstrating that

Conclusion

The neurotransmitter 5-HT is critically involved in the regulation of multiple physiological and pathophysiological functions in the central nervous system and the periphery. Serotonin operates via a heterogenic receptor family that includes fourteen different mammalian 5-HT receptors. With the exception of the 5-HT₃R, which is a cation channel, all 5-HT receptors belong to the GPCR superfamily and are coupled to different intracellular effectors via multiple heterotrimeric G proteins. During

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Citation Excerpt :
It should also be noted that 5-HT5A receptors seem to be weakly coupled to G proteins compared to other Gi/Go protein-coupled 5-HT receptors (Masson et al., 2012). At the same time that some 5-HT receptors have been less studied, the 5-HT6 receptors has attracted increasing attention over the past decade (Ivachtchenko et al., 2016; Wirth et al., 2017). The high affinity of the 5-HT6 receptors for certain antipsychotic drugs and its profuse distribution in limbic and cortical regions signal it them as a promising target for the treatment of various neurological and neurodegenerative diseases (Monsma et al., 1993; Ruat et al., 1993a; Gérard et al., 1997; Yoshioka et al., 1998; Woolley et al., 2004; Yun and Rhim, 2011).
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Review articleHow serotonin receptors regulate morphogenic signalling in neurons

Highlights

Abstract

Section snippets

Discovery of serotonin and its receptors

Morphogenic signalling by defined 5-HT receptors

Conclusion

Trends Endocrinol. Metab. TEM

J. Biol. Chem.

Brain Res.

Off. Publ. Am. Coll. Neuropsychopharmacol.

Brain Res.

J. Biol. Chem.

Neuropharmacology

Eur. J. Pharmacol.

Cell

J. Biol. Chem.

Physiol. Behav.

Neuron

Neuroscience

Off. Publ. Am. Coll. Neuropsychopharmacol

Neuropharmacology

Neuroscience

Neuropharmacology

J. Biol. Chem.

Brain Res.

Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol.

Neuron

Biol. Psychiatry

Eur. J. Pharmacol.

Exp. Neurol.

Neuron

Curr. Opin. Pharmacol.

Neuropharmacology

Biol. Psychiatry

Trends Neurosci.

Neuropsychopharmacology

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Pharmacol. Ther.

Brain Res.

Dev. Biol.

Exp. Neurol.

Nucl. Med. Biol.

Brain Res.

Brain Res.

Neuroscience

Cloning of another human serotonin receptor (5-HT1F): a fifth 5-HT1 receptor subtype coupled to the inhibition of adenylate cyclase

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

Growth retardation and altered autonomic control in mice lacking brain serotonin

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

Serotonin mediates CA1 spine density but is not crucial for ovarian steroid regulation of synaptic plasticity in the adult rat dorsal hippocampus

Synapse

5-Hydroxytryptamine 1A and 2B serotonin receptors in neurite outgrowth: involvement of early growth response protein 1

Dev. Neurosci.

Regional changes in density of serotonin transporter in the brain of 5-HT1A and 5-HT1B knockout mice, and of serotonin innervation in the 5-HT1B knockout

J. Neurochem.

Development and adult plasticity of serotoninergic neurons and their target cells

Serotonin-mediated endocytosis of apCAM: an early step of learning-related synaptic growth in Aplysia

Science

A clinicopathological study of autism

Brain J. Neurol.

Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone

Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol.

5-Hydroxytryptamine4 receptor activation of the extracellular signal-regulated kinase pathway depends on src activation but not on G protein or β-Arrestin signaling

Mol. Biol. Cell

Review article
How serotonin receptors regulate morphogenic signalling in neurons