THE HUMAN MELANOCYTE-STIMULATING HORMONE-RECEPTOR HAS EVOLVED TO BECOME SUPER-SENSITIVE TO MELANOCORTIN PEPTIDES

Melanocyte-stimulating hormone (MSH) stimulates pigmentation in mammals by activating specific cell surface MSH receptors (MC1-Rs) on melanocytes. MC1-Rs on normal human melanocytes have been difficult to detect and characterise. The pharmacological characterisation of a cloned human MC1-R (hMC1-R) is reported here, and directly compared with that of a cloned mouse MC1-R (mMC1-R). The human and mouse MC1-Rs are equally sensitive (EC(50) = 1-2 pM) to the super potent analogue of alpha-MSH, NDP-MSH. In contrast with the mMC1-R, the hMC1-R is also very sensitive to alpha-MSH (EC(50) = 2 pM), ACTH (EC(50) = 8 pM), and Lys gamma(3)-MSH (EC(50) < 10(-10) M). This suggests that in man, in contrast with rodents, both ACTH and Lys gamma(3)-MSH may have physiological roles in pigmentation.