Serotonylation and Transamidation of Other Monoamines

Although serotonin was discovered over 65 years ago, it has been only within the past decade that serotonin was found to be involved in a covalent post-translational modification to proteins. The enzyme transglutaminase catalyzes the transamidation of serotonin to a protein-bound glutamine residue; the amino group of serotonin is covalently bound to the gamma carboxamide of glutamine. The term serotonylation is used to describe this transamidation reaction to serotonin. Not only can serotonin be a substrate for transamidation to proteins but also other monoamine neurotransmitters are substrates including histamine, dopamine, and noradrenaline. The term monoaminylation has been coined to describe the transamidation of monoamines to protein substrates. Small G proteins have emerged as the most common substrate for monoaminylation and are activated by this post-translational modification. Fibronectin and cytoskeletal proteins are also substrates for monoaminylation. Serotonylation and monoaminylation are involved in a number of physiological functions, including platelet activation, insulin release, smooth muscle contraction, and regulation of membrane localization of the serotonin transporter. Stimulation of 5-HT2A receptors increases serotonylation and activates the small G protein Rac1, which plays a role in dendritic spine regulation. Monoaminylation is implicated in pathophysiological processes as well such as diabetes and hypertension. The availability of monoamines for monoaminylation is altered by antidepressants that target serotonin transporters, noradrenaline transporters, or the enzymatic degradation of monoamines as well as drugs of abuse such as cocaine and amphetamines. Further research on monoaminylation is needed to elucidate its physiological and pathophysiological roles and to explore monoaminylation as a novel target for drug therapy.