Diazepam enhances melanogenesis, melanocyte dendricity and melanosome transport via the PBR/cAMP/PKA pathway

Int J Biochem Cell Biol. 2019 Nov:116:105620. doi: 10.1016/j.biocel.2019.105620. Epub 2019 Sep 24.

Abstract

Diazepam is a medicament of the benzodiazepine family and it typically produces a sedative effect. Researchers have revealed that diazepam can induce melanogenesis and produce dendrite-like structures in B16 melanoma cells. However, the associated mechanisms of melanogenesis and phenotypic alterations have mostly remained unknown. In this study, we determined the effects of diazepam on melanogenesis, cellular phenotypic alterations, the location of melanosomes and the expression of relevant proteins in melanocytes using Masson-Fontana ammoniacal silver staining, scanning electron microscopy, immunocytochemistry and western blot analysis. Our results collectively indicated that diazepam had a pivotal role in melanocytes by enhancing melanin synthesis, melanocyte dendricity, melanosome trafficking, and capture at the dendrite tips. These functions might be attributed to the fact that diazepam activated the peripheral benzodiazepine receptor (PBR). This increased intracellular levels of cAMP, which stimulated the phosphorylation of cAMP response element-binding (CREB). As a result, this increased the tyrosinase, microphthalmia-associated transcription factor (MITF), Rab27a, Myosin Va, Rab17 and Cdc42 expression. This caused melanogenesis and melanosome transport. Therefore, our findings may provide a potential strategy for treating anti-hypopigmentation disorders.

Keywords: Diazepam; Melanogenesis; Melanosome transport; PBR; cAMP/PKA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport / drug effects
  • CREB-Binding Protein / genetics
  • CREB-Binding Protein / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / genetics*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Diazepam / pharmacology*
  • Gene Expression Regulation
  • Humans
  • Hypnotics and Sedatives / pharmacology*
  • Melanocytes / cytology
  • Melanocytes / drug effects*
  • Melanocytes / metabolism
  • Melanosomes / drug effects*
  • Melanosomes / metabolism
  • Mice
  • Microphthalmia-Associated Transcription Factor / genetics
  • Microphthalmia-Associated Transcription Factor / metabolism
  • Monophenol Monooxygenase / genetics
  • Monophenol Monooxygenase / metabolism
  • Myosin Heavy Chains / genetics
  • Myosin Heavy Chains / metabolism
  • Myosin Type V / genetics
  • Myosin Type V / metabolism
  • Receptors, GABA-A / genetics*
  • Receptors, GABA-A / metabolism
  • Signal Transduction
  • cdc42 GTP-Binding Protein / genetics
  • cdc42 GTP-Binding Protein / metabolism
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism
  • rab27 GTP-Binding Proteins / genetics
  • rab27 GTP-Binding Proteins / metabolism

Substances

  • Hypnotics and Sedatives
  • MITF protein, human
  • Microphthalmia-Associated Transcription Factor
  • Myo5a protein, mouse
  • Receptors, GABA-A
  • rab27 GTP-Binding Proteins
  • Cyclic AMP
  • Monophenol Monooxygenase
  • CREB-Binding Protein
  • CREBBP protein, human
  • Cyclic AMP-Dependent Protein Kinases
  • Myosin Type V
  • Rab17 protein, mouse
  • RAB27A protein, human
  • Myosin Heavy Chains
  • CDC42 protein, human
  • cdc42 GTP-Binding Protein
  • rab GTP-Binding Proteins
  • Diazepam