Protoporphyrin IX Stimulates Melanogenesis, Melanocyte Dendricity, and Melanosome Transport Through the cGMP/PKG Pathway.

Jinpeng Lv,Rongyin Gao,Xiaohong An,Songzhou Jiang,Guoqiang Song,Ying Yang

doi:10.3389/fphar.2020.569368

Abstract

Protoporphyrin IX (PPIX) is a heterocyclic organic compound that is the last intermediate in the heme biosynthetic pathway. PPIX, due to its photodynamic effects, is utilized in the treatment of skin diseases. Furthermore, PPIX has been utilized as a melanogenesis-stimulating agent in various studies. However, the exact function and mechanism underlying PPIX action in melanocytes remain to be elucidated. In the present study, we sought to further investigate how PPIX affects melanocyte melanogenesis, and whether PPIX is involved in melanin transport. Our findings demonstrated that PPIX increased melanocyte dendricity and melanosome transport, in addition to increasing melanogenesis. PPIX functions primarily by activating the guanylate cyclase (GC) and cyclic guanosine 3’, 5’-monophosphate/protein kinase G (cGMP/PKG) signaling pathways. Once activated, these pathways increase tyrosinase activity and the expression of microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 and -2 (TRP-1 and TRP-2), myosin Va, melanophinin, Ras-related protein Rab-27A (Rab27a), and cell division cycle 42 (Cdc42), promoting melanogenesis, melanocyte dendricity, and melanosome transport. Furthermore, the melanogenic effects of PPIX were confirmed in vivo in a zebrafish model system. Our results indicate that PPIX is not cytotoxic and may, thus, be utilized as a pigmentation enhancer.

Highlights

In humans, melanin originating from melanocytes plays a variety of valuable physiological functions, with the most important being the protection of the human skin against damage from ultraviolet (UV) radiation (Raposo and Marks, 2007; Noguchi et al, 2014)
Microphthalmia-associated transcription factor (MITF), a key activator of the tyrosinase promoter, is a master transcription factor that activates the transcription of pigmentation genes and is required for melanocyte proliferation and survival (Lee et al, 2013; Lv et al, 2020), whereas kinesin family member 5b (KIF5b) functions as a motor that regulates outward melanosome transport along microtubules (Hara et al, 2000; Hirokawa et al, 2009). >>myosin Va-melanophilin-Ras– related protein Rab-27A (Rab27a) complexes contribute to melanosome transport along actin filaments, while Rab27Amelanophinin complex is responsible for anchoring melanosomes transferred to the cell membrane (Ohbayashi and Fukuda, 2012)
Protoporphyrin IX (PPIX) is a heterocyclic organic compound that consists of four pyrrole rings and is the immediate precursor to heme (Sachar et al, 2016)

Summary

Introduction

Melanin originating from melanocytes plays a variety of valuable physiological functions, with the most important being the protection of the human skin against damage from ultraviolet (UV) radiation (Raposo and Marks, 2007; Noguchi et al, 2014). Cell division cycle 42 (Cdc42) contributes to dendrite extension, a crucial requirement for melanosome transport (Luo, 2000) Environmental stimuli, such as UV irradiation, play an important role in melanogenesis and dendrite extension (Abdel-Naser et al, 2003). When a-MSH binds to melanocortin-1 receptor (MC1R) in melanocytes, it can activate adenylate cyclase (AC), increase the intracellular cyclic adenosine monophosphate (cAMP) levels, and subsequently activate the protein kinase A (PKA)/cAMP-responsive element-binding (CREB) pathway, promoting melanogenesis (Corre et al, 2004; Rzepka et al, 2016). UV radiation directly activates guanylate cyclase (GC), increases the intracellular levels of cyclic guanosine monophosphate (cGMP), and subsequently activates the protein kinase G (PKG)/CREB pathway, promoting melanogenesis (Romero-Graillet et al, 1996)

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Results

Conclusion