Abstract
The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor involved in neurodegenerative and inflammatory disorders. RAGE induces cellular signaling upon binding to a variety of ligands. Evidence suggests that RAGE up-regulation is involved in quinolinate (QUIN)-induced toxicity. We investigated the QUIN-induced toxic events associated with early noxious responses, which might be linked to signaling cascades leading to cell death. The extent of early cellular damage caused by this receptor in the rat striatum was characterized by image processing methods. To document the direct interaction between QUIN and RAGE, we determined the binding constant (Kb) of RAGE (VC1 domain) with QUIN through a fluorescence assay. We modeled possible binding sites of QUIN to the VC1 domain for both rat and human RAGE. QUIN was found to bind at multiple sites to the VC1 dimer, each leading to particular mechanistic scenarios for the signaling evoked by QUIN binding, some of which directly alter RAGE oligomerization. This work contributes to the understanding of the phenomenon of RAGE-QUIN recognition, leading to the modulation of RAGE function.
Highlights
Neurodegenerative disorders represent one of the most important causes of disability in the world
A recent study indicated that QUIN induces up-regulation of receptor for advanced glycation end products (RAGE), leading to the activation of the NF-ĸB pathway, altered gene expression, nitrosative stress, metabolic alterations and premature cell damage [11]. These results suggested that the up-regulation of RAGE may play a role in the early stages of QUIN toxicity, which is mostly attributed to a direct action of QUIN on N-methyl-D-aspartate receptor (NMDAr) and a further indirect activation of RAGE
RAGE is commonly associated with pro-inflammatory responses that provoke neurodegeneration, the precise mechanisms involved in those pathways triggered by the interaction of the receptor and its ligands remain unsolved
Summary
Neurodegenerative disorders represent one of the most important causes of disability in the world. The persistent activation of glutamatergic NMDAr and the concomitant excitotoxic event induced by QUIN have been linked with a cascade of toxic processes that kill neuronal cells These processes include oxidative stress, inflammation, neurochemical deficits, and energy depletion, among others [8]. Early toxic events that will be responsible for late toxicity are of major relevance to understand neurodegenerative processes One of these mechanisms could be related with the stimulation of deadly cascades toward the direct activation of different membrane receptors, independently of an action on NMDAr. Our group has recently described preliminary evidence of the involvement of the receptor for advanced glycation end products (RAGE) in the toxic pattern exerted by QUIN in the rat striatum [11]. We were able to demonstrate that RAGE expression was increased by QUIN, comprising the trigger of a proinflammatory pathway; whether QUIN might interact directly with RAGE to enhance toxicity is a question deserving further investigation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
