Transglutaminase 2-mediated serotonylation in pulmonary hypertension

Abstract

The monoamine serotonin (5-HT) has been previously implicated in pulmonary arterial remodeling and is considered a potential therapeutic target for the disease pulmonary arterial hypertension (PAH). More recently, it has been recognized that the enzyme tissue transglutaminase (TG2) mediates cross-linking of proteins with 5-HT, a posttranslational process of monoaminylation known as "serotonylation." TG2 activity and serotonylation of protein participate in both smooth muscle proliferation and contraction produced by 5-HT. Indeed, markedly increased TG2 activity has now been identified in lung tissue of an experimental rodent model of pulmonary hypertension, and elevated serotonylation of fibronectin and the signaling molecule Rho, downstream products of transglutamidation, have been found in blood of patients with PAH. The basic mechanism by which TG2 is activated and the potential role(s) of serotonylated proteins in pulmonary hypertension remain a mystery. In the present review we have tried to address the current understanding of 5-HT metabolism in pulmonary hypertension and relate it to what is currently known about the evolving cellular process of serotonylation.

Keywords: pulmonary hypertension; serotonin; serotonylation; transglutamidation; transglutaminase 2.

Fig. 1.

Scheme of 5-HT pathway showing hydroxylation of tryptophan by the rate-limiting enzyme tryptophan hydroxylase (Tph) to 5-hydroxytryptophan (5-HTP). 5-HTP is then decarboxylated to 5-HT by the enzyme aromatic amino acid decarboxylase (AAAD). 5-HT is metabolized to its inactive metabolite 5-hydroxyindoleacetic acid (5HIAA) by a 2-step enzymatic process involving monoamine oxidase and aldehyde dehydrogenase.

Fig. 2.

Summary for the hypothesis of combinatorial 5-HT-related cell signaling pathways. 2A, 5-HT2A receptor; 5HTT, serotonin transporter; BMPR, bone morphogenetic protein receptor; ERK, extracellular signal-related kinase; PDGFR, plaetlet-derived growth factor receptor; PI3K, phosphatidylinositide 3-kinase; Rho, Ras homolog gene; TF, transcription factor; ROS, reactive oxygen species; mTOR, mammalian target of rapamycin.

Fig. 3.

Schematic illustration of serotonylation of transglutaminase (TG2) substrate protein by 5-HT. This posttranslational modification is catalyzed by the TG2 enzyme resulting in formation of serotonylated protein and ammonia.