Description Table of Contents Product Details Click on the cover image above to read some pages of this book! Melanocortin Signalling Mechanisms Paula C. Eves and John W. Schaub, Erin B. Dmt The Spirit Molecule. In Stock. Introduction to Research in the Health Sciences 6th Edition. Understanding Research in Clinical and Counseling Psychology. Introduction to Meta-Analysis.
Item Added: Melanocortins. View Wishlist. My belief is so strong that I left academia to form a company based on -MSH analogs and have caused millions of dollars to be spent on melanocortin research.
Now why would a sane professor pick up such a challenge and enter business, an essential step toward any clinical application? It is the - MSH story that drove me. Consider that - MSH occurs in exactly the same amino acid sequence in humans and in the sea lamprey, an organism unchanged since its appearance during the Pennsylvanian period of the Paleozoic era about million years ago—way before dinosaurs were to be considered.
All compounds augmented efferocytosis of human apoptotic neutrophils by primary macrophages statistically significant for DTrp , as compared with non-treated ctrl cells Figure 1C. We also quantified multiple ingestions, as they reflect the effectiveness of dead cells clearance i. Together, the clearance index showed increased effectiveness in apoptotic cell clearance for all compounds. Bias plots were then constructed by representing one pathway against the other Figure 2B.
This effect of BMS reported as an MC 1 -selective drug is of particular relevance, as it highlights the importance of measuring signaling outcomes other than the canonical cAMP to confidently attribute receptor selectivity to a molecule. Association between signaling cascades and functional effects of melanocortin drugs on macrophages. The analysis was performed by Pearson correlation test.
Strength of the association is denoted by both color and size of bubble darker color and bigger size meaning higher correlation; red, negative; blue positive. We could then highlight several associations that may help elucidate the contribution of each receptor type and signaling pathways to functional outcomes Figure 2C. For example, the only receptor positively associated with both reduction in cytokines and increased phagocytosis was MC 1 highlighted in magenta.
Strikingly, cAMP pathway at all receptors was negatively associated with cytokine reduction highlighted in purple. The analysis of phagocytosis also revealed new clues about the relevant signaling that may drive this effect. G-protein coupled receptor GPCRs activation is a highly dynamic process where receptor proteins can acquire multiple active states evoking distinct signaling pathways Kroeze et al.
The complex pharmacology of these receptors is determined by properties like ligand promiscuity, temporal pathways network activation, desensitization, ligand independent activation, allosteric modulation or ligand bias Melancon et al. Here we performed a systematic analysis selecting two major biological actions of MCR agonists and studied their association positive or negative with two signaling readouts. In fact, our findings represent a challenge against the current dogma on cAMP drug discovery approaches, assuming cAMP as the major, or even the only pathway used to inform candidate selection.
Currently, all drug screening programs on MC drug discovery are based on cAMP accumulation, despite the lack of consistent evidence that this pathway is indeed the most therapeutically relevant one, at least to develop new anti-inflammatory agents. Thus, this promising candidate currently on phase I trial—CT would have been filtered out in a typical cAMP-based screening.
Correlation analyses need to be interpreted considering that association does not imply causation. Therefore, more in-depth analyses are necessary to fully understand associations between receptors-pathways-functions to inform drug discovery programs to prevent decisions based on assumptions. Furthermore, macrophages express multiple melanocortin receptors which are activated simultaneously by a given agonist.
However, drug discovery screenings are usually performed on a single target basis using transfected cell as we did here. TM-M conceived the study. SP and JG-M contributed to the experimental methods.
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TM-M contributed to the visualization. TM-M and MP wrote the manuscript. TM-M supervised the study.
- Structure-activity relationships (SAR) of melanocortin and agouti-related (AGRP) peptides.
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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Buch, T. Pertussis toxin-sensitive signaling of melanocortin-4 receptors in hypothalamic GT cells defines agouti-related protein as a biased agonist. Ferrante, C.
Central inhibitory effects on feeding induced by the adipo-myokine irisin. Anorexigenic effects induced by RVD-hemopressin alpha administration. Kenakin, T. Signalling bias in new drug discovery: detection, quantification and therapeutic impact.
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