Regulation of Transglutaminase by 5-HT2A Receptor Signaling and Calmodulin
type: CreativeWork
description: Transglutaminase (TGase), nature’s biological glue, catalyzes the post-translational modification of proteins by formation of intra- and intermolecular protein cross-links or by primary amine incorporation. TGase has various physiological functions, such as skin-barrier formation and blood clot stabilization, whereas increasing evidence indicates they may also involved in neurodegenerative diseases including Huntington’s disease (HD), Alzheimer disease’s, and progressive supranuclear palsy. Mutant huntingtin (htt) and small G proteins (e.g. Rac 1) are potential substrates of TGases. The purpose of this dissertation was to characterize the mechanisms by which 5-HT2A receptor signaling and calmodulin (CaM) regulate TGase-catalyzed transamidation of Rac1 and htt in cultured neuronal cells and HD transgenic animals, respectively. 5-HT2A receptors are G-protein coupled receptors which are widely expressed in the brain, peripheral vasculature, platelets and skeletal muscle. They are involved in diverse physiological functions, from platelet aggregation to neuroendocrine release. In A1A1v cells, a rat cortical cell line, stimulation of 5-HT2A receptor induces small G protein Rac1 transamidation and activation. An inhibitory agent or knockdown of TGase by siRNA revealed that TGase is responsible for transamidation and activation of Rac1. Moreover, serotonin was identified as an amine that becomes transamidated to Rac1 by TGase. The classical signal transduction pathway of 5-HT2A receptors is Gq/11-coupled activation of phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3) and diacyglycerol. IP3 mobilizes Ca2+ from the endoplasmic reticulum and thereby increases intracellular Ca2+ and consequently, it may enhance TGases enzymatic activity. Inhibition of PLC or manipulation of intracellular Ca2+ by a chelating agent suppressed 5-HT2A receptor-mediated Rac1 transamidation, whereas an elevation in intracellula…
abstract: Transglutaminase (TGase), nature’s biological glue, catalyzes the post-translational modification of proteins by formation of intra- and intermolecular protein cross-links or by primary amine incorporation. TGase has various physiological functions, such as skin-barrier formation and blood clot stabilization, whereas increasing evidence indicates they may also involved in neurodegenerative diseases including Huntington’s disease (HD), Alzheimer disease’s, and progressive supranuclear palsy. Mutant huntingtin (htt) and small G proteins (e.g. Rac 1) are potential substrates of TGases. The purpose of this dissertation was to characterize the mechanisms by which 5-HT2A receptor signaling and calmodulin (CaM) regulate TGase-catalyzed transamidation of Rac1 and htt in cultured neuronal cells and HD transgenic animals, respectively. 5-HT2A receptors are G-protein coupled receptors which are widely expressed in the brain, peripheral vasculature, platelets and skeletal muscle. They are involved in diverse physiological functions, from platelet aggregation to neuroendocrine release. In A1A1v cells, a rat cortical cell line, stimulation of 5-HT2A receptor induces small G protein Rac1 transamidation and activation. An inhibitory agent or knockdown of TGase by siRNA revealed that TGase is responsible for transamidation and activation of Rac1. Moreover, serotonin was identified as an amine that becomes transamidated to Rac1 by TGase. The classical signal transduction pathway of 5-HT2A receptors is Gq/11-coupled activation of phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3) and diacyglycerol. IP3 mobilizes Ca2+ from the endoplasmic reticulum and thereby increases intracellular Ca2+ and consequently, it may enhance TGases enzymatic activity. Inhibition of PLC or manipulation of intracellular Ca2+ by a chelating agent suppressed 5-HT2A receptor-mediated Rac1 transamidation, whereas an elevation in intracellula…
author: Dai, Ying
keywords: calcium, gene therapy, Huntington's disease, Rac1, serotonin, transamidation, Neuroscience and Neurobiology
date published: 2009-01-01T08:00:00Z
date modified: 2026-07-24T02:55:08Z
provider: Loyola University Chicago
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Loyola University Chicago