Melanocortin receptor 4 (MC4R) is expressed predominantly in the central nervous system and regulates food intake and sexual function and is also thought to be responsible for effects on mood and cogn Show more
Melanocortin receptor 4 (MC4R) is expressed predominantly in the central nervous system and regulates food intake and sexual function and is also thought to be responsible for effects on mood and cognition. It belongs to the melanocortin receptor subfamily of G protein-coupled receptors (GPCRs). Here, we have synthesized and structurally characterized three peptides that bind to MC4R, producing different signaling events. AgRP is a naturally occurring antagonist, HLWNRS is the minimal sequence of the N-terminal with partial agonist activity, and aMSH is a full agonistic peptide. By implementing molecular dynamics simulations on the different peptide-receptor complexes, we propose their molecular basis of binding to investigate their differential molecular properties regarding the activation states of the receptor. Our analysis shows that the agonist and partial agonist may induce rotation in transmembrane helix 3, which is known to be involved in the key events occurring during GPCR activation, and this movement is impacted by certain aromatic residues and their positioning in the orthosteric binding site of the receptor. Show less
Nogo-A and its putative receptor NgR are considered to be among the inhibitors of axonal regeneration in the CNS. However, few studies so far have addressed the issue of local NgR complex multilateral Show more
Nogo-A and its putative receptor NgR are considered to be among the inhibitors of axonal regeneration in the CNS. However, few studies so far have addressed the issue of local NgR complex multilateral localization within inflammation in an MS mouse model of autoimmune demyelination. Chronic experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice. Analyses were performed on acute (days 18-22) and chronic (day 50) time points and compared to controls. The temporal and spatial expression of the Nogo receptor complex (NgR and coreceptors) was studied at the spinal cord using epifluorescent and confocal microscopy or real-time PCR. Data are expressed as cells/mm Animals developed a moderate to severe EAE without mortality, followed by a progressive, chronic clinical course. NgR complex spatial expression varied during the main time points of EAE. NgR with coreceptors LINGO-1 and TROY was increased in the spinal cord in the acute phase whereas LINGO-1 and p75 signal seemed to be dominant in the chronic phase, respectively. NgR was detected on gray matter NeuN Our data describe in detail the expression of the Nogo receptor complex within the autoimmune inflammatory foci and suggest a possible immune action for NgR apart from the established inhibitory one on axonal growth. Its expression by inflammatory macrophages/monocytes could signify a possible role of these cells on axonal guidance and clearance of the lesioned area during inflammatory demyelination. Show less