Diabetes mellitus is one of the most important metabolic disorders and is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism, resulting from defects in insulin secretion, insulin action, or both. However, many aspects of insulin secretion remain elusive for the complex machinery involved, in particular the role of serotonin (5-HT) in endocrine pancreatic b-cells. It is known for more than three decades that 5-HT co-localizes with insulin in the secretory granules of these cells and it is co-released when pancreatic islets are stimulated with glucose. Nevertheless, the function of 5-HT in this context was not identified so far. 5-HT is a neurotransmitter of major importance as well as a peripheral hormone that regulates essential mood-related, metabolic and cardiovascular processes. The serotonergic system is unique amongst monoaminergic (neuro-)hormonal systems for its biosynthesis via two distinct rate-limiting tryptophan hydroxylases in the brain (TPH2) and peripheral tissues (TPH1).

The generation of Tph1-/- mice has allowed us to identify a previously unknown receptor-independent signalling mechanism of 5-HT in thrombocytes, which we have termed "serotonylation". This transglutaminase-dependent mechanism constitutively activates small GTPases by covalent binding of 5-HT to a glutamine residue of their catalytic centre, thereby triggering the exocytosis of a-granules from thrombocytes. Mice lacking peripheral 5-HT biosynthesis have a wide spectrum of physiological phenotypes, such as impaired primary haemostasis and liver regeneration, and diabetes. However, reduced 5-HT levels also exert protective effects within the cardiovascular system, e. g. in primary pulmonary hypertension.

In the presentation it will be shown that serotonylation of small GTPases of the Rab family modulates insulin secretion from pancreatic b-cells. Tph1-/- mice show altered insulin secretion, resulting in glucose intolerance as well as mild fasting hyperglycaemia. Together with its early onset and the inheritable pattern, this phenotype can be classified as maturity-onset diabetes of the young. Thus, monoaminylation (serotonylation) of small GTPases seems to be a crucial mechanism in the fine tuning of insulin secretion. This is the third microserotonergic system that has so far been described to depend on this posttranslational protein modification, adding strong evidence to our view, that monoaminylation plays a decisive modulatory role in signalling within a broad variety of tissues under physiological conditions.