Cyclodextrin induces calcium-dependent lysosomal exocytosis

PLoS One. 2010 Nov 29;5(11):e15054. doi: 10.1371/journal.pone.0015054.

Abstract

Cyclodextrins (CDs) have long been used to manipulate cellular cholesterol levels both in vitro and in vivo, but their direct effects at a cellular level are not well characterized. Recently, CDs have garnered much interest because of their ability to clear stored cholesterol from Niemann Pick Type C (NPC) cells and markedly prolong the life of NPC1 disease mice. Here, we investigate the hypothesis that treatment with 2-hydroxypropyl- β-cyclodextrin (HPB-CD) stimulates lysosomal exocytosis in a calcium-enhanced manner. We propose that this exocytosis is the mechanism by which HPB-CD ameliorates the endolysosomal cholesterol storage phenotype in NPC cells. These findings have significant implications for the use of HPB-CD in biochemical assays and data interpretation as well as for their use for the treatment for NPC and other disorders.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin
  • Animals
  • Blotting, Western
  • Calcium / metabolism*
  • Cell Line
  • Cell Survival / drug effects
  • Cholesterol / metabolism
  • Excipients / pharmacology
  • Exocytosis / drug effects*
  • Exosomes / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Lysosomes / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Microscopy, Fluorescence
  • Proteins / genetics
  • Proteins / metabolism
  • beta-Cyclodextrins / pharmacology*
  • beta-N-Acetylhexosaminidases / metabolism

Substances

  • Excipients
  • Intracellular Signaling Peptides and Proteins
  • Npc1 protein, mouse
  • Proteins
  • beta-Cyclodextrins
  • Green Fluorescent Proteins
  • 2-Hydroxypropyl-beta-cyclodextrin
  • Cholesterol
  • Extracellular Signal-Regulated MAP Kinases
  • beta-N-Acetylhexosaminidases
  • Calcium