Vitamin D signaling and the differentiation of developing dopamine systems

Neuroscience. 2016 Oct 1;333:193-203. doi: 10.1016/j.neuroscience.2016.07.020. Epub 2016 Jul 20.

Abstract

Vitamin D regulates multiple factors including those involved in the ontogeny of dopaminergic systems. It has been shown that in neonatal rats maternally deprived of vitamin D, dopamine (DA) turnover is decreased with associated reductions in one catabolic enzyme, catechol-o-methyl transferase (COMT). To directly examine this signaling relationship, in the present study we have over-expressed the vitamin D receptor (VDR) in neuroblastoma SH-SY5Y cells in order to examine the mechanisms by which the active vitamin D hormone, 1,25(OH)2D3, via its receptor VDR, affects DA production and turnover. Our results show that VDR overexpression increases DA neuron differentiation by increasing tyrosine hydroxylase expression, DA production and decreasing the expression of NEUROG2 a marker of immature DA neurons. In the VDR-overexpressing cells, 1,25(OH)2D3 further increased the levels of the DA-metabolites 3-MT and HVA and elevated COMT gene expression. Chromatin immunoprecipitation revealed that 1,25(OH)2D3 increased VDR binding in three regions of the COMT promoter, strongly suggesting direct regulation. In addition, 1,25(OH)2D3 treatment attenuated increased levels of MAOA, DRD2 and VMAT2 gene expression caused by the VDR-overexpression. Taken together, these results show VDR and 1,25(OH)2D3 are directly involved in regulating the expression of dopaminergic-associated genes and that this in vitro neuronal model is a useful tool for identifying the role of 1,25(OH)2D3 in DA neuronal development and maturation.

Keywords: COMT; SH-SY5Y; development; dopamine; vitamin D receptor (VDR); vitamin D,1,25(OH)(2)D(3).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Catechol O-Methyltransferase / genetics
  • Catechol O-Methyltransferase / metabolism
  • Cell Line, Tumor
  • Dopamine / analogs & derivatives
  • Dopamine / metabolism
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism*
  • Humans
  • Monoamine Oxidase / metabolism
  • Nerve Tissue Proteins / metabolism
  • Neurogenesis / drug effects
  • Neurogenesis / physiology*
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Receptors, Calcitriol / metabolism*
  • Receptors, Dopamine D2 / metabolism
  • Tyrosine 3-Monooxygenase / metabolism
  • Vesicular Monoamine Transport Proteins / metabolism
  • Vitamin D / administration & dosage
  • Vitamin D / analogs & derivatives*
  • Vitamin D / metabolism
  • Vitamins / administration & dosage

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • DRD2 protein, human
  • NEUROG2 protein, human
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Receptors, Calcitriol
  • Receptors, Dopamine D2
  • SLC18A2 protein, human
  • VDR protein, human
  • Vesicular Monoamine Transport Proteins
  • Vitamins
  • Vitamin D
  • 1,25-dihydroxyvitamin D
  • Tyrosine 3-Monooxygenase
  • Monoamine Oxidase
  • monoamine oxidase A, human
  • COMT protein, human
  • Catechol O-Methyltransferase
  • 3-methoxytyramine
  • Dopamine