Elsevier

Brain Research Bulletin

Volume 56, Issue 5, 15 November 2001, Pages 413-424
Brain Research Bulletin

Article
Modern views on an ancient chemical: serotonin effects on cell proliferation, maturation, and apoptosis

https://doi.org/10.1016/S0361-9230(01)00614-1Get rights and content

Abstract

Evolutionarily, serotonin existed in plants even before the appearance of animals. Indeed, serotonin may be tied to the evolution of life itself, particularly through the role of tryptophan, its precursor molecule. Tryptophan is an indole-based, essential amino acid which is unique in its light-absorbing properties. In plants, tryptophan-based compounds capture light energy for use in metabolism of glucose and the generation of oxygen and reduced cofactors. Tryptophan, oxygen, and reduced cofactors combine to form serotonin. Serotonin-like molecules direct the growth of light-capturing structures towards the source of light. This morphogenic property also occurs in animal cells, in which serotonin alters the cytoskeleton of cells and thus influences the formation of contacts. In addition, serotonin regulates cell proliferation, migration and maturation in a variety of cell types, including lung, kidney, endothelial cells, mast cells, neurons and astrocytes). In brain, serotonin has interactions with seven families of receptors, numbering at least 14 distinct proteins. Of these, two receptors are important for the purposes of this review. These are the 5-HT1A and 5-HT2A receptors, which in fact have opposing functions in a variety of cellular and behavioral processes. The 5-HT1A receptor develops early in the CNS and is associated with secretion of S-100β from astrocytes and reduction of c-AMP levels in neurons. These actions provide intracellular stability for the cytoskeleton and result in cell differentiation and cessation of proliferation. Clinically, 5-HT1A receptor drugs decrease brain activity and act as anxiolytics. The 5-HT2A receptor develops more slowly and is associated with glycogenolysis in astrocytes and increased Ca++ availability in neurons. These actions destabilize the internal cytoskeleton and result in cell proliferation, synaptogenesis, and apoptosis. In humans, 5-HT2A receptor drugs produce hallucinations. The dynamic interactions between the 5-HT1A and 5-HT2A receptors and the cytoskeleton may provide important insights into the etiology of brain disorders and provide novel strategies for their treatment.

Introduction

Serotonin has been implicated in more behaviors, physiological mechanisms, and disease processes than any other brain neurotransmitter. The enormous range of this single brain chemical system may reflect the vast distribution of its fibers in brain, from a small group of large multipolar neurons. The neurons form a collection of clustered cells termed the raphe nuclei, located on the exact midline of the brainstem. Serotonergic fibers interact in complex ways with a variety of cell types—neurons, glial cells, endothelial cells, ependymal cells and others—by binding to at least 14 distinct receptor proteins. Furthermore, serotonin neurons are one of the first brainstem neurons to emerge during early development of the brain and spinal cord—present by the sixth week of gestation in humans. In rats, 5-hydroxytryptamine (5-HT) neurons in the brainstem raphe are among the first neurons to differentiate in the brain and play a key role in regulating neurogenesis [64]. The serotonin neurons are the first neuronal system to innervate the primordial cortical plate. During development, 5-HT fibers arrive at the cortical plate during the peak period of mitosis and maturation [42]. Lauder and Krebs [65] reported that para-chlorophenylalanine (PCPA), a 5-HT synthesis inhibitor, retarded neuronal maturation, while mild stress, a releaser of hormones, accelerated neuronal differentiation. These workers defined differentiation as the cessation of cell division measured by incorporation of 3H-thymidine. Since then, many other workers have shown a role for serotonin in neuronal differentiation, (e.g., 54, 74 and references contained in Whitaker-Azmitia, this issue). Certainly, all these facts suggest a critical role for serotonin in brain function, but is there really something distinct about serotonin, as a chemical?

Serotonin is synthesized from tryptophan, which contains an indole ring and a carboxyl-amide side-chain, similar to all amino acids. The indole ring, however, is unique in that it is composed of both a benzene ring and a secondary pentane ring having a central nitrogen. The indole ring, and therefore tryptophan itself, is capable of absorbing light. In plants, tryptophan produces receptor proteins which harness light and thus produce biologically important molecules [61]. Chlorophyll, for example, captures light because it contains tryptophan, and then generates ATP, reduced cofactors (NADH), and oxygen. This entire process is blocked if tryptophan is substituted with another amino acid [84]. Furthermore, in plants tryptophan itself is converted into the tropic factor auxin, by removing the amide group to make indole-acetic acid. Auxin stimulates changes in cell shape and provides movement for plants. The position of the leaves is regulated by auxin, in order that they face the source of light energy, normally the sun (Fig. 1). Thus tryptophan plays a role in capturing energy and in the positioning of the plant to maximize light absorption. This biosynthetic interaction between tryptophan and light may be maintained throughout evolution. For example, in the mammalian brain, serotonin and melatonin, which are synthesized from tryptophan, act to entrain endogenous rhythms to the light cycle [79].

The effects of serotonin on morphology have long been known. For more than 50 years, serotonin has been known to constrict blood vessels (indeed, this is the origin of the name) [95] and induce shape changes in skeletal muscle (at both the light and electron microscope level) [93], platelets [69], endothelial cells [121], and fibroblast [28]. In the periphery, serotonin originates largely from mast cells, which can produce, release, and re-uptake serotonin. The released serotonin may then act as a chemotactic, increase vascular permeability, cause vasodilatation, and smooth muscle spasm [82].

In addition to its role in morphological changes, serotonin also has been shown to play a role in cell proliferation. In cultured rat pulmonary artery smooth muscle cells (SMC), serotonin induces DNA synthesis and potentiates the mitogenic effect of platelet-derived growth factor-BB [45]. Serotonin effects on cell proliferation may involve the phosphorylation of GTPase-activating protein (GAP), an intermediate signal in serotonin-induced mitogenesis of SMC [68].

The biological mechanism used by serotonin to change cell morphology and induce proliferation may directly target the cytoskeleton. The main component of the cytoskeleton, which gives cells their shape, is microtubules. These microtubules consist of long polymers of tubulin, which spontaneously depolymerize if they are not actively polymerizing [83]. In 1975, Tan and Lagnado [116] found effects of serotonin and related indole alkaloids on brain microtubular proteins. Several years later, it was found that serotonin is taken up by endothelial cells and binds to stress fibers [7]. Here serotonin induces actin polymerization and affects changes in the cytoskeleton. Thus, there is evidence serotonin has a direct role in regulating and maintaining microtubules and microfilaments. The changes reported in serotonin-induced cytoskeletal stability may be partially mediated by microtubule-associated proteins (MAPs). MAPs serve to stabilize the cytoskeleton by binding to tubulin polymers and inhibiting their depolymerization. In undifferentiated human neuroblastoma cells (LAN-5), high levels of serotonin (50 uM) induce a decrease while low levels of serotonin (50 nM) induce an increase in the cytoplasmic tau protein, a MAP found in high concentrations in the axon of neurons [60]. Thus, there is evidence that serotonin is involved in a variety of cellular processes involved in regulating metabolism, proliferation and morphology. The fine integration of these dynamic events appears to involve multiple receptor action.

Section snippets

Advent of receptors

With time, cells developed crude receptor molecules to open ion channels and regulate intermediate metabolism within the cell by regulating cAMP and Ca++ levels. Molecular biologist have sequenced over 50 distinct receptor proteins recognizing serotonin. In this chapter, we will discuss only two mammalian receptors in detail, the 5-HT1A and the 5-HT2A receptor. In the brain and spinal cord, serotonin acts on the 5-HT1A and 5-HT2A receptors to regulate neuronal morphology and apoptosis in the

Astroglial cells

These cells are central to any discussion of plasticity within the brain, since they not only make glucose available to neurons, but also provide adhesion and trophic factors for neuronal growth and migration. Merzak and co-workers [81] found 5-HT1A receptor mRNA in human normal fetal astrocytes by reverse transcription and polymerase chain reaction (RT-PCR). Hirst and co-workers [57] also used reverse transcriptase-polymerase chain reaction to show the expression of 5-HT1A receptor in

Cell proliferation

The role of both the 5-HT1A and 5-HT2A receptors during development suggest influences on cell proliferation [32]. Although many factors are involved in determining mitosis, the importance of the cytoskeleton, especially the spindle apparatus, is central.

The spindle apparatus is composed of tubulin, exactly like the microtubules involved in cellular structure. In fact, the tubulin used in the construction of the spindle apparatus is actually taken from the microtubules of the cytoskeleton. When

5-HT1A receptor

Apoptosis, or programmed cell death, can be induced in immature neurons by a variety of methods. The cells exposed to apoptotic-inducing conditions may actually up-regulate 5-HT1A receptors. Neuronal cell lines stably transfected with a promoter-less segment (G-21) of the human 5-HT1A receptor (5-HT1A-R) gene [112] show a 5 to 15-fold increase in the receptor when deprived of nutrient. The temporal correlation between degeneration and the expression of the 5-HT1A receptor is reminiscent of the

Implications for drug discovery

This chapter has not only reviewed the evolutionary role and a function of serotonin, but also advances the notion that serotonin plays a major role in the plasticity of the brain. We have used two receptors, the 5-HT1A and the 5-HT2A, to show how serotonin can produce opposite and complimentary actions on neuronal functioning (Fig. 2), maturation (Fig. 3), proliferation (Fig. 4), and apoptosis fig. 5, FIG. 6. The action of the 5-HT1A receptor on the release of S100β offers a unique mechanism

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