Sortilin, a member of the family of Vps10p domain receptors, has been shown to be able to bind the precursor peptide of nerve growth factor (proNGF). ProNGF interacts with sortilin and the p75 NTR receptor on the cell surface to form a molecular complex capable of activating an apoptotic cascade. Keratinocytes can secrete proNGF and they have p75 NTR on their surface. The expression of sortilin in normal human keratinocytes has not yet been clearly shown. In this study, we show that

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... s express sortilin mRNA, and the presence of sortilin protein is shown in cultured keratinocytes and in normal human skin. We have also shown that the cutaneous neuropeptides substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide, and galanin are able to reduce the expression of sortilin mRNA and sortilin protein in cultured human keratinocytes. In addition, each of the analyzed neuropeptides has the ability to arrest the proNGF-induced apoptosis of human keratinocytes. These results suggest that all the participants in the NGF/proNGF pathway are present in the keratinocytes, and cutaneous neuropeptides can modulate their expressions and actions. The NGF/proNGF balance and its regulation by neuropeptides may have an important role in skin homeostasis. Abbreviations: CGRP, calcitonin gene-related peptide; GAL, galanin; NGF, nerve growth factor; proNGF, precursor nerve growth factor; SP, substance P; VIP, vasoactive intestinal polypeptide Bull HA, Leslie TA, Chopra S et al. (1998) Expression of nerve growth factor receptors in cutaneous inflammation. Brit J Dermatol 139:776-83 Burbach GJ, Kim KH, Zivony AS et al. (2001) The neurosensory tachykinins substance P and neurokinin A directly induce keratinocyte nerve growth factor. J Invest Dermatol 117:1075-82 Canuel M, Lefrancois S, Zeng J et al. (2008) AP-1 and retromer play opposite roles in the trafficking of sortilin between the Golgi apparatus and the lysosomes. Biochem Biophys Res Commun 366:724-30 Chang SE, Han SS, Jung HJ et al. (2007) Neuropeptides and their receptors in psoriatic skin in relation to pruritus. Br J Dermatol 156:1272-7 Dallos A, Kiss M, Polyanka H et al. (2006a) Effects of the neuropeptides substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide and galanin on the production of nerve growth factor and inflammatory cytokines in cultured human keratinocytes. Neuropeptides 40:251-63 Dallos A, Kiss M, Polyanka H et al. (2006b) Galanin receptor expression in cultured human keratinocytes and in normal human skin. J Peripher Nerv Syst 11:156-64 www.jidonline.org 2559 M Kiss et al.