Serotonylation is a biological process that involves the attachment of serotonin to proteins. This mechanism is distinct from serotonin’s more commonly recognized role as a neurotransmitter that interacts with receptors on cell surfaces. Instead, serotonylation represents a post-translational modification, meaning it alters proteins after they have been synthesized. This modification allows serotonin to directly influence intracellular processes by forming long-lasting covalent bonds with proteins.
The Molecular Process of Serotonylation
Serotonylation occurs when serotonin is covalently linked to specific proteins, primarily at their glutamine residues. This enzymatic reaction is catalyzed by a family of enzymes called transglutaminases (TGases), which form a robust glutamyl-amide bond between serotonin and the target protein. Tissue transglutaminase 2 (TG2) is a prominent enzyme involved in intracellular serotonylation, while coagulation factor XIIIa (FXIIIa) facilitates the modification of proteins like fibrinogen in platelets.
The attachment of serotonin to a protein can lead to either reversible or irreversible modifications. While generally considered irreversible, some evidence suggests a mechanism for reversal. This modification takes place after serotonin is transported into the cell, rather than at the plasma membrane where serotonin typically interacts with its receptors.
Serotonylation’s Role in Cellular Function
Serotonylation directly impacts protein activity and cellular signaling pathways by altering the structure and function of modified proteins. One significant role is in blood clotting, where serotonylation of small GTPases like Rab4 and RhoA in platelets triggers the release of alpha-granules, promoting platelet aggregation. Serotonylation of fibrinogen gamma chain (FGG) in platelets also contributes to the formation of more stable fibrin clots, accelerating thrombogenesis.
This modification also extends to metabolic processes, influencing insulin secretion from pancreatic beta cells. Serotonylation of small GTPases, such as Rab3a and Rab27a, enhances glucose-mediated insulin release, explaining why defects in transglutaminase can lead to glucose intolerance. Beyond these, serotonylation has been observed to modify cytoskeletal proteins, contributing to the regulation of vascular smooth muscle tone in blood vessels.
Serotonylation has emerged as a novel epigenetic factor, affecting gene expression. It involves the attachment of serotonin to histone proteins. This modification can lead to long-lasting changes in cellular function and gene expression, potentially influencing processes like neuronal differentiation and T-cell activation.
Serotonylation and Human Health
Dysregulation of serotonylation pathways has been linked to various health conditions. In cardiovascular health, serotonylation plays a role in pulmonary hypertension, where it influences the proliferation of pulmonary vascular smooth muscle cells. The process can affect the contractility of blood vessels, impacting conditions like hypertension.
In metabolic disorders, the link between serotonylation and insulin secretion suggests its involvement in conditions such as diabetes and obesity. Impaired serotonylation of proteins involved in glucose metabolism can contribute to glucose intolerance. Understanding these pathways could lead to new therapeutic strategies for managing blood glucose levels.
While research is ongoing, serotonylation may also have implications for neurological conditions. For instance, in hippocampal neurons, serotonylation of RhoA has been shown to modulate synaptic plasticity, which is related to learning and memory processes. Targeting serotonylation pathways offers a promising avenue for developing new treatments for a range of diseases, including those affecting the cardiovascular system, metabolism, and potentially the brain.