PROTEIN MONOAMINYLATION: NEWLY RECOGNIZED FUNCTIONS OF MONOAMINERGIC HORMONES

After the finalization of the human genome project, investigations into the transcriptome, proteome, and metabolome have been largely increased, since their concurrence determines the functionality of genes. In this context, recent mechanistic discoveries have induced a kind of “paradigm shift” regarding the mode of action of hormones and widened our understanding of these compounds in cell and gene regulation, particularly when involved in human diseases. (Scientific Report 2007 of the Max Planck Society)

Nine low-molecular weight neurotransmitters have been identified in the central nervous system of vertebrates and four of them are evolutionary ancient primary monoamines with very short biosynthetic pathways starting from biogenic L-amino acids. Serotonin [5-hydroxytryptamine (5-HT)], one of these nine neurotransmitters, is not only the messenger of some thousands of neurons, but an ubiquitous substance in peripheral tissues and fluids, from which 5-HT was first isolated 58 years ago identifying it as the vasoconstrictor compound in serum (serotonin: tonin contained in serum) that had been postulated for over eight decades by then, and appears in conjunction with platelet degranulation. Tryptophan hydroxylase (TPH), a member of the family of aromatic amino acid hydroxylases (AAAHs), catalyzes the rate-limiting step in the biosynthesis of 5-HT biasing the serotonergic system in its whole. 5-HT is a neurotransmitter functioning also as a hormone and growth factor, particularly in early embryonic development.

Mitogenic effects of 5-HT in adult tissues are also gaining attention, for example, in the pathological hyperplasia of the pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary hypertension. However, the underlying mechanisms for such processes have remained elusive, while a growing body of evidence points to a crucial involvement of the 5-HT transporter (SERT) in the etiology of this disease.

A dichotomy of the serotonergic system consisting of two 5-HT-synthesizing TPH isoforms was recently characterized, using Tph gene-targeted (Tph1-/-) mice. TPH1, the enzyme known for decades, is broadly expressed in non-neuronal tissues and the novel TPH2 is almost restricted to neurons. Furthermore, a novel intracellular mechanism of 5-HT signaling was discovered in the viable Tph1-/- mice, a mechanism depending on the SERT-driven entry of 5-HT into cells in conjunction with Ca²⁺ mobilization, which culminates in the constitutively activating covalent modification of small GTPases of the Rho and Rab families with 5-HT in a transglutaminase-mediated reaction. This posttranslational protein modification was termed ‘serotonylation’. In addition, other biogenic monoamines, such as histamine (HA), dopamine (DA), and norepinephrine (NE) can cause an analogous transglutaminase-mediated activation of signaling proteins, wherefore the general term ‘monoaminylation’ was coined.

Our group is focused on the elucidation of molecular mechanisms causing human diseases by the generation, analysis, and rescue experiments of transgenic and knockout mouse models. Currently we work on animals with defined genetic dysfunctions in the serotonergic system and related biochemical pathways, aiming the elucidation of the numerous hormonal and neurotransmitter effects of 5-HT. Furthermore, we study vesicular trafficking and the involved signal transduction, for example, using platelets as model system for neuronal vesicular processes. Another field is the use of harmless prodrugs that are enzyme-specifically toxified in tissues expressing either endogeneous tryptophan hydroxylase or transgenic nitroreductase of E. coli to induce defined lesions in tissues of interest.

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