9.A.14.2.3
Melanocortin receptor 4, MC4R, of 332 aas and 7 TMSs. At least 4% of childhood obesity is due to mutations in the hypothalamic MC4R which is important in the regulation of feeding behavior and body weight. MC4R activates the Galphaq/phospholipase C signaling pathway, resulting in alterations of cytoplasmic calcium in immortalized hypothalamic (GT1-1)neurons. Thus, upon agonist binding, MC4R mediates increases in intracellular calcium through the Galphaq-protein/phospholipase C dependent signaling pathway (Newman et al. 2006).  MC4R binds to two neuropeptides, α-melanocyte-stimulating hormone [αMSH] and agouti-related protein [AgRP] which exert opposing effects on downstream responses.  The 3-D structure of MC4R complexed with the cyclic peptide antogonist, SHU9119, revealed a Ca²⁺-binding site that influences downstream signaling (Chaturvedi and Shukla 2020). Israeli et al. 2021 presented the cryo-EM structure of the human MC4R-G_s signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity. The work reveals the mechanism of MC4R activation, highlighting a molecular switch that initiates satiation signaling. Calcium (Ca²⁺) is required for agonist, but not antagonist, efficacy (Israeli et al. 2021).  MC4R and TMEM18 (TC# 9.B.228) transcript abundances in sperm were positively correlated with the spermatozoa oxidative status (Correia et al. 2022).