Novel roles for biogenic monoamines: from monoamines in transglutaminase‐mediated post‐translational protein modification to monoaminylation deregulation diseases

Functional protein serotonylation is a newly recognized post‐translational modification with the primary biogenic monoamine (PBMA) serotonin (5‐HT). This covalent protein modification is catalyzed by transglutaminases (TGs) and, for example, acts in the constitutive activation of small GTPases. Multiple physiological roles have been identified since its description in 2003 and, importantly, deregulated serotonylation was shown in the etiology of bleeding disorders, primary pulmonary hypertension and diabetes. The PBMAs 5‐HT, histamine, dopamine, and norepinephrine all act as neurotransmitters in the nervous system and as hormones in non‐neuronal tissues, which points out their physiological importance. In analogy to serotonylation we have found that also the other PBMAs act through the TG‐catalyzed mechanisms of ‘histaminylation’, ‘dopaminylation’ and ‘norepinephrinylation’. Therefore, PBMAs deploy a considerable portion of their effects via protein monoaminylation in addition to their canonical receptor‐mediated signaling. Here, the implications of these newly identified post‐translational modifications are presented and discussed. Furthermore, the potential regulatory roles of protein monoaminylation in small GTPase, heterotrimeric G‐protein and lipid signaling, as well as in modulating metabolic enzymes and nuclear processes, are critically assessed.