Intracellular Serotonin Modulates Insulin Secretion from Pancreatic β-Cells by Protein Serotonylation

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Author SummaryDiabetes is the most prevalent metabolic disease and one that affects individuals of every social and economic status. The disease can arise as a result of reduced secretion of insulin from pancreatic β-cells or reduced action of insulin on its target organs. Therefore, understanding how to prevent and treat diabetes requires an extensive knowledge of the regulation of insulin secretion. In this study, we identify the hormone serotonin as a new regulator of insulin secretion and thereby attribute a function to the co-localization of serotonin and insulin in pancreatic β-cells that was first observed 30 years ago but until now not understood. We first demonstrate that a lack of serotonin in β-cells of transgenic mice leads to reduced insulin secretion and diabetes mellitus and that pharmacological replenishment of serotonin rescues insulin secretion in these mice. Interestingly, serotonin mainly acts not as an intercellular signaling molecule via its traditional surface receptors but intracellularly via regulation of the activity of target proteins through covalent coupling of serotonin to them. This coupling, called serotonylation, activates specific small GTPases, which in turn promote glucose-mediated insulin secretion. Adding this receptor-independent signaling mechanism to the multifarious regulatory functions of serotonin, we hypothesize that protein serotonylation modulates physiological secretion processes in all serotonin-containing tissues.