title: Nicotinic acid receptor abnormalities in human skin cancer: implications for a role in epidermal differentiation.
abstract: BACKGROUND
  Chronic UV skin exposure leads to epidermal differentiation defects in humans that can be largely restored by pharmacological doses of nicotinic acid. Nicotinic acid has been identified as a ligand for the human G-protein-coupled receptors GPR109A and GPR109B that signal through G(i)-mediated inhibition of adenylyl cyclase. We have examined the expression, cellular distribution, and functionality of GPR109A/B in human skin and skin derived epidermal cells.
  
  
  RESULTS
  Nicotinic acid increases epidermal differentiation in photodamaged human skin as judged by the terminal differentiation markers caspase 14 and filaggrin. Both GPR109A and GPR109B genes are transcribed in human skin and in epidermal keratinocytes, but expression in dermal fibroblasts is below limits of detection. Receptor transcripts are greatly over-expressed in squamous cell cancers. Receptor protein in normal skin is prominent from the basal through granular layers of the epidermis, with cellular localization more dispersive in the basal layer but predominantly localized at the plasma membrane in more differentiated epidermal layers. In normal human primary and immortalized keratinocytes, nicotinic acid receptors show plasma membrane localization and functional G(i)-mediated signaling. In contrast, in a squamous cell carcinoma derived cell line, receptor protein shows a more diffuse cellular localization and the receptors are nearly non-functional.
  
  
  CONCLUSIONS
  The results of these studies justify future genetic and pharmacological intervention studies to define possible specific role(s) of nicotinic acid receptors in human skin homeostasis.
authors.affiliation: Arizona Cancer Center and Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Yira
authors.initials: Y
authors.lastname: Bermudez
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Benavente
authors.forename: Ralph G
authors.initials: RG
authors.lastname: Meyer
authors.forename: W Russell
authors.initials: WR
authors.lastname: Coyle
authors.forename: Myron K
authors.initials: MK
authors.lastname: Jacobson
authors.forename: Elaine L
authors.initials: EL
authors.lastname: Jacobson
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D000091344:Filaggrin Proteins; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism; D009525:Niacin / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; C530636:HCAR2 protein, human; C473653:HCAR3 protein, human; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D009525:Niacin; D000242:Cyclic AMP