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A Phylogenetic Study On The Activation Mechanism of MC5R By The Pituitary Hormone ACTH

There is a family of biological receptors on cells called the melanocortin receptors (MCRs). These five receptors are activated by the hormone ACTH and have a variety of different functions in cells, including helping an organism recover from a chronic stress event. Both MC2R, which aids in stress recovery, and MC5R share a common ancestral gene, so it was hypothesized that they would have similar pharmacological properties, specifically in activation.To study this, Chinese hamster ovary cells were transiently transfected with species specific MC5R and MRAP, the accessory protein to MCRs. The cells were then stimulated with varying alanine-substituted ACTH analogs to see if MC5R requires both motifs (HFRW and KKRRP) on ACTH for full activation. We found that stingray MC5R seems to require only the HFRW motif and that chicken MC5R seems to rely heavily on the HFRW motif but the KKRRP motif also appears to play a role. As MC2R requires a two-step mechanism for activation, it seems that MC5R may not follow suit; rather, MRAP may aid in full activation for MC5R more so than the KKRRP motif, which provides new pharmacological opportunities if future studies support our results.