the implications of these variants on the function of the The cloning and characterization of the human melanocortin-1 receptor (MC1R) and the demonstration that normal human MC1R revealed the following. Human melanocytes homelanocytes respond to the melanocortins, a-melanocyte stimmozygous for Arg160Trp mutation in the MC1R demonulating hormone (a-MSH) and adrenocorticotrophic hormone strated a significantly reduced response to a-MSH. Also, this culture responded poorly to ASP and exhibited an exagger-(ACTH), with increased proliferation and eumelanogenesis ated cytotoxic response to UVR. Another culture, which was had put an end to a long-standing controversy about the role homozygous for Val92Met mutation in the MC1R, demonof melanocortins in regulating human cutaneous pigmentation. strated a normal response to a-MSH. Heterozygous mutaWe have shown that a-MSH and ACTH bind the human tions that are frequently expressed in various melanocyte MC1R with equal affinity, and are equipotent in their mitocultures did not disrupt MC1R function. These results begin genic and melanogenic effects on human melanocytes. We also to elucidate the significance of MC1R variants in the function showed that the activation of the MC1R is important for the of the receptor. Our data emphasize the significance of a melanogenic response of human melanocytes to ultraviolet normally functioning MC1R in the response of melanocytes to radiation (UVR). The MC1R is also the principal mediator of melanocortins, ASP, and UVR. the inhibitory effects of agouti signaling protein (ASP) on melanogenesis. Expression of the MC1R is subject to regulation by its own ligands a-MSH and ACTH, as well as by Key words: Melanocortin 1 receptor, Human melanocytes, Ultraviolet radiation, Melanocortins, Agouti signaling protein, UVR and endothelin-1. Recent studies that we conducted on the expression of MC1R variants by human melanocytes and Eumelanin, Pheomelanin that have an extensive amino acid sequence homology. These peptides include a-melanocyte stimulating hormone (a-MSH), b-MSH, g-MSH, and adrenocorticotrophic hormone (ACTH), all of which are derived from a large precursor peptide, pro-opiomelanocortin (POMC) (1). The 4-10 carboxy teminus amino acid residues of a-MSH, b-MSH,

Small GTPases of the Rab family are key regulators of membrane trafficking. Each Rab shows a characteristic subcellular distribution, and may serve as an important determinant of organelle identity. The molecular mechanisms responsible for targeting Rabs to specific intracellular compartments, however, remain poorly understood. The divergent C-terminal hypervariable region was postulated to contain Rab targeting information. We generated a series of hybrid Rab proteins by exchanging the hypervariable domains of Rab1a, Rab2a, Rab5a, Rab7 and Rab27a, and analysed their subcellular localisations. We found that the various hybrid proteins retained their targeting to the parent organelle and were functionally active. We conclude that the hypervariable region does not contain a general Rab targeting signal. Furthermore, we identified other regions within the RabF and RabSF motifs that are required for specific targeting of Rab27a to secretory granules or melanosomes, and Rab5a to endosomes. We observed only partial overlap between targeting-determining regions in the Rab proteins examined, suggesting that Rab recruitment may be complex and at least partially Rab-specific. Mutations in these targeting-determining regions induced localisation to the ER, an observation that further strengthens our previous finding that ER/Golgi membranes serve as the default location for Rabs that have lost targeting information.

Rab38(cht/cht) mice show ocular characteristics reminiscent of human oculocutaneous albinism, as well as iris and RPE thinning. The synergistic effects of the Rab38(cht) and Tyrp1(b) alleles suggest that TYRP1 is not the only target of RAB38 trafficking. This mouse line provides a useful model for studying melanosome biology and its role in human ocular diseases.