The melanocortin receptor signaling system and its role in neuroprotection against neurodegeneration: Therapeutic insights

Abstract The melanocortin signaling system consists of the melanocortin peptides, their distinctive receptors, accessory proteins, and endogenous antagonists. Melanocortin peptides are small peptide hormones that have been studied in a variety of physiological and pathological conditions. There are five types of melanocortin receptors, and they are distributed within the central nervous system and in several tissues of the periphery. The G protein–coupled melanocortin receptors typically signal through adenylyl cyclase and other downstream signaling pathways. Depending on the ligand, surface expression of melanocortin receptor, receptor occupancy period, related proteins, the type of cell, and other parameters, the signaling pathways are complicated and pleiotropic. While it is known that all five melanocortin receptors are coupled to Gs, they can also occasionally couple to Gq or Gi. Both direct and indirect neuroprotection are induced by the melanocortin signaling system. Targeting several of the components of the melanocortin signaling system (ligands, receptors, accessory proteins, signaling effectors, and regulators) may provide therapeutic opportunities. Activation of the melanocortin system improves different functional traits in neurodegenerative diseases. There is a potential for additional melanocortin system interventions by interfering with dimerization or dissociation. This review aims to discuss the melanocortin receptor signaling system and its role in neuroprotection, as well as its therapeutic potential.