Alpha-, beta-, and gamma-
melanocyte stimulating hormones (MSHs) are
melanotropin peptides that are derived from the
ACTH/
beta-endorphin prohormone
proopiomelanocortin (
POMC). They have been highly conserved through evolutionary development, although their functions in mammals have remained obscure. The identification in the last decade of a family of five membrane-spanning
melanocortin receptors (MC-Rs), for which the melanotropins are the natural
ligands, has permitted the characterization of a number of important actions of these
peptides, although the physiological function(s) of
gamma-MSH have remained elusive. Much evidence indicates that
gamma-MSH stimulates sympathetic outflow and raises blood pressure through a central mechanism. However, this review focuses on newer cardiovascular and renal actions of the
peptide, acting in most cases through the MC3-R. In rodents, a high-
sodium diet (HSD) increases the pituitary abundance of
POMC mRNA and of
gamma-MSH content and results in a doubling of plasma
gamma-MSH concentration. The
peptide is natriuretic and acts through renal MC3-Rs, which are also upregulated by the HSD. Thus the system appears designed to participate in the integrated response to
dietary sodium excess. Genetic or pharmacologic induction of
gamma-MSH deficiency results in marked
salt-sensitive
hypertension that is corrected by the administration of the
peptide, probably through a central site of action. Deletion of the MC3-R also produces
salt-sensitive
hypertension, which, however, is not corrected by infusion of the
hormone. These observations in aggregate suggest the operation of a hormonal system important in blood pressure control and in the regulation of
sodium excretion. The relationship of these two actions to each other and the significance of this system in humans are important questions for future research.