Serotonin: More than a neurotransmitter

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Abstract

Serotonin (5-HT) is a signalling molecule with a multitude of functions in the central nervous system and in the periphery. Serotonin synthesis from tryptophan is initiated by the rate-limiting enzyme tryptophan hydroxylase (TPH). We have previously discovered that two TPH isoenzymes exist in all vertebrates, TPH1 and TPH2, encoded by two distinct genes1,2. TPH1 is mainly expressed in the gut generating serotonin that is distributed into the whole body by thrombocytes, and in the pineal gland, where the resulting 5-HT is metabolized to melatonin. TPH2, on the other hand, is responsible for the synthesis of serotonin in the raphé nuclei of the brain stem, from where all serotonergic projections originate. In order to characterize the functions of serotonin in the brain and in the periphery, we have generated knockout mice for both isoforms^2,3.
Tph1-deficient mice revealed that 95% of peripheral serotonin is produced by TPH1. They also showed that serotonin in platelets and other peripheral cells is involved in such diverse processes as thrombosis⁴, liver regeneration⁵, hepatitis⁶, colon cancer⁷, mammary gland plasticity⁸, and pulmonary hypertension⁹.
Tph1-deficient mice lack 99% of serotonin in the brain but have normal levels in the periphery. Surprisingly, and in contrast to animals lacking other neurotransmitter systems, these mice can be born and even survive until adulthood. However, depletion in serotonin signaling in the brain leads to dwarfism and 50% lethality in the first weeks of postnatal life in these mice. Telemetric monitoring revealed more extended daytime sleep, suppressed respiration, altered body temperature control and decreased blood pressure and heart rate during nighttime in Tph2-/- mice. Moreover Tph2-/- females, despite being fertile and producing milk, exhibit impaired maternal care leading to poor survival of their pups. Thus Tph2-/- animals represent a unique model to clarify the functional importance of the neurotransmitter serotonin.
The data already obtained from these mice confirm the strict duality of the serotonin system and demonstrate that central serotonin is not essential for life but is a pivotal modulator of numerous autonomic pathways.

References
1. Walther,D.J. & Bader,M. A unique central tryptophan hydroxylase isoform. Biochem. Pharmacol. 66, 1673-1680 (2003)
2. Walther,D.J. et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299, 76 (2003)
3. Alenina,N. et al., Growth retardation and altered autonomic control in mice lacking brain serotonin. PNAS 106: 10332-10337 (2009)
4. Walther,D.J. et al. Serotonylation of small GTPases is a signal transduction pathway that triggers platelet -granule release.  Cell 115, 851-862 (2003)
5. Lesurtel,M. et al. Platelet-derived serotonin mediates liver regeneration. Science 312, 104-107 (2006)
6. Lang,P.A. et al. Aggravation of viral hepatitis by platelet-derived serotonin. Nat.Med. 14,756-761 (2008)
7. Nocito,A. et al. Serotonin regulates macrophage-mediated angiogenesis in a mouse model of colon cancer allografts. Cancer Res. 68, 5152-5158 (2008)
8. Matsuda,M. et al. Serotonin regulates mammary gland development via a novel autocrine-paracrine loop. Dev. Cell 6, 193-203 (2004)
9. Morecroft,I. et al. Effect of tryptophan hydroxylase 1 deficiency on the development of hypoxia-induced pulmonary hypertension. Hypertension 49, 232-236 (2007)

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