Transthyretin oligomers induce calcium influx via voltage-gated calcium channels

J Neurochem. 2007 Jan;100(2):446-57. doi: 10.1111/j.1471-4159.2006.04210.x. Epub 2006 Oct 31.


The deposition of transthyretin (TTR) amyloid in the PNS is a major pathological feature of familial amyloidotic polyneuropathy. The aim of the present study was to examine whether TTR could disrupt cytoplasmic Ca(2+) homeostasis and to determine the role of TTR aggregation in this process. The aggregation of amyloidogenic TTR was examined by solution turbidity, dynamic light scattering and atomic force microscopy. A nucleation-dependent polymerization process was observed in which TTR formed low molecular weight aggregates (oligomers < 100 nm in diameter) before the appearance of mature fibrils. TTR rapidly induced an increase in the concentration of intracellular Ca(2+) ([Ca(2+)](i)) when applied to SH-SY5Y human neuroblastoma cells. The greatest effect on [Ca(2+)](i) was induced by a preparation that contained the highest concentration of TTR oligomers. The TTR-induced increase in [Ca(2+)](i) was due to an influx of extracellular Ca(2+), mainly via L- and N-type voltage-gated calcium channels (VGCCs). These results suggest that increasing [Ca(2+)](i) via VGCCs may be an important early event which contributes to TTR-induced cytotoxicity, and that TTR oligomers, rather than mature fibrils, may be the major cytotoxic form of TTR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels / physiology*
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology
  • Extracellular Fluid / drug effects
  • Extracellular Fluid / metabolism
  • Fura-2 / metabolism
  • Humans
  • Microscopy, Atomic Force / methods
  • Mutation / physiology
  • Neuroblastoma / pathology
  • Prealbumin / chemistry*
  • Prealbumin / physiology*
  • Protein Structure, Quaternary / physiology
  • Thapsigargin / pharmacology
  • Time Factors
  • Transfection / methods


  • Calcium Channel Blockers
  • Calcium Channels
  • Enzyme Inhibitors
  • Prealbumin
  • Thapsigargin
  • Calcium
  • Fura-2