Substance P Stimulates Endothelin 1 Secretion via Endothelin-Converting Enzyme 1 and Promotes Melanogenesis in Human Melanocytes

Abstract

Substance P (SP) is a well-known neuropeptide implicated in the wound-healing process. The wound occasionally causes a pigmented scar. In the present study, we examined whether increased levels of SP affected melanogenesis. When human melanocytes were treated with SP, the melanin content increased and the pigmentation process accelerated in a dose-dependent manner. In addition to melanogenesis-related genes, the expression of neurokinin 1 receptor, endothelin 1 (EDN1), and EDN receptor type B (EDNRB) also increased at both the messenger RNA and protein levels. Interestingly, secreted EDN1 was observed in the melanocyte culture medium, and this phenomenon was significantly enhanced by SP treatment. Through knockdown experiments using small interfering RNAs (siRNAs), we confirmed that endothelin-converting enzyme 1 (ECE1), EDN1, and EDNRB were involved in SP-induced pigmentation and found that EDN1 secretion was affected by ECE1 and EDN1 siRNAs, but not by EDNRB siRNA. These findings indicate that ECE1 is essential for EDN1 secretion in melanocytes and that EDNRB functions downstream of secreted EDN1 to increase the cAMP levels and activate the melanogenesis-related phosphorylation cascade. This study provides in vitro evidence for a melanogenic function of SP in the skin and suggests that the SP-related signal is a potent target for regulating stress- or wound-induced pigmentation.

Paracrine regulation of melanogenesis

“…9,10 In addition, an intimate relationship between the cutaneous nervous system and melanocytes has been reported. [11][12][13] In this article, we review the intricate interactions between melanocytes and their surrounding environment that regulate melanogenesis, focusing on the secretory molecules.…”

“…Endothelins (EDNs) are secreted mainly from keratinocytes and bind to EDN receptors on melanocytes to regulate melanogenesis . In response to UV, expression of EDNs is highly elevated to enhance the signalling cascades, among which the EDN1–EDN receptor type B (EDNRB) pathway is considered to play significant role in UVB‐induced pigmentation by modulating MITF phosphorylation in normal human melanocytes …”

“…Intraepidermal nerve endings intimately interact with epidermal melanin units by secreting certain neuropeptides (Fig. ) . Among these neuropeptides, calcitonin gene‐related peptide (CGRP) can induce melanocyte proliferation and melanogenesis via induction of keratinocyte‐derived melanogenic cytokines in organ‐cultured human skin and cultured normal human melanocytes.…”

“…36 In response to UV, expression of EDNs is highly elevated to enhance the signalling cascades, among which the EDN1-EDN receptor type B (EDNRB) pathway is considered to play significant role in UVB-induced pigmentation by modulating MITF phosphorylation in normal human melanocytes. 12,37,38 Nitric oxide (NO), a kind of diffusible free radical gas synthesized by the enzyme NO synthase, is considered to be a main intracellular and intercellular messenger molecule in different cells and tissues. 39 The stimulatory melanogenic effect of paracrine factors produced by keratinocytes in response to UV has been reported to be markedly blocked by NO scavengers in normal human melanocyte and keratinocyte cocultures, suggesting an important role of NO in UV-induced melanogenesis.…”

“…Furthermore, several studies have shown that extracellular matrix (ECM) proteins, which are responsible for structure formation and the transduction of cellular signalling pathways in the skin, can affect melanogenesis . In addition, an intimate relationship between the cutaneous nervous system and melanocytes has been reported . In this article, we review the intricate interactions between melanocytes and their surrounding environment that regulate melanogenesis, focusing on the secretory molecules.…”