Abstract
AimN-acyl dopamines (NADD) are gaining attention in the field of inflammatory and neurological disorders. Due to their hydrophobicity, NADD may have access to the endoplasmic reticulum (ER). We therefore investigated if NADD induce the unfolded protein response (UPR) and if this in turn influences cell behaviour.MethodsGenome wide gene expression profiling, confirmatory qPCR and reporter assays were employed on human umbilical vein endothelial cells (HUVEC) to validate induction of UPR target genes and UPR sensor activation by N-octanoyl dopamine (NOD). Intracellular ATP, apoptosis and induction of thermotolerance were used as functional parameters to assess adaptation of HUVEC.ResultsNOD, but not dopamine dose dependently induces the UPR. This was also found for other synthetic NADD. Induction of the UPR was dependent on the redox activity of NADD and was not caused by selective activation of a particular UPR sensor. UPR induction did not result in cell apoptosis, yet NOD strongly impaired cell proliferation by attenuation of cells in the S-G2/M phase. Long-term treatment of HUVEC with low NOD concentration showed decreased intracellular ATP concentration paralleled with activation of AMPK. These cells were significantly more resistant to cold inflicted injury.ConclusionsWe provide for the first time evidence that NADD induce the UPR in vitro. It remains to be assessed if UPR induction is causally associated with hypometabolism and thermotolerance. Further pharmacokinetic studies are warranted to address if the NADD concentrations used in vitro can be obtained in vivo and if this in turn shows therapeutic efficacy.
Highlights
The endoplasmic reticulum (ER) can be considered as the gatekeeper for protein synthesis, assuring appropriate protein folding and maturation of secreted and transmembrane proteins
Whenever the folding capacity of the ER is too low to meet the cellular demand for newly synthesized proteins, unfolded or misfolded proteins start to accumulate in the ER, which in turn, triggers a set of responses known as the unfolded protein response (UPR) [1,2,3,4]
UPR sensor activation is characterized by cleavage of X-boxbinding protein 1 (Xbp1) mRNA (IRE1), phosphorylation of the translation initiation factor 2 a subunit (PERK) and processing of activating transcription factor 6 (ATF6) in the Golgi apparatus [6,7,8,9,10,11,12] The UPR has been implicated in a variety of diseases including cancer, metabolic, neurodegenerative and inflammatory diseases [13]
Summary
The endoplasmic reticulum (ER) can be considered as the gatekeeper for protein synthesis, assuring appropriate protein folding and maturation of secreted and transmembrane proteins. The UPR consist of three different branches, each of which containing a specific transmembrane ER sensor protein that, upon activation, sets a series of responses in motion resulting in the transcription of typical UPR target genes [3,4] These so called UPR sensor proteins are the inositol requiring kinase 1 (IRE1), double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) and activating transcription factor 6 (ATF6) [1,2,3], all of which are associated with the ER chaperone glucoseregulated protein BiP. Signalling components of the UPR are emerging as potential targets for intervention and treatment of human disease [15]
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.
