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Single-Cell Calcium Imaging for Studying the Activation of Calcium Ion Channels
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Transthyretin oligomers induce calcium influx via voltage-gated calcium channels

Xu Hou1, Helena C Parkington, Harold A Coleman

  • 1Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.

Journal of Neurochemistry
|November 2, 2006
PubMed

Insights

Transthyretin (TTR) oligomers disrupt nerve cell calcium homeostasis, increasing intracellular calcium via specific channels. This TTR oligomer-induced calcium influx may drive neurotoxicity in familial amyloidotic polyneuropathy.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Cell Biology

Background:

  • Familial amyloidotic polyneuropathy involves transthyretin (TTR) amyloid deposition in the peripheral nervous system (PNS).
  • The precise mechanisms by which TTR contributes to neurotoxicity are not fully understood.

Purpose of the Study:

  • To investigate if TTR disrupts cytoplasmic calcium homeostasis.
  • To determine the role of TTR aggregation in this disruption and its potential contribution to cytotoxicity.

Main Methods:

  • Examined TTR aggregation using solution turbidity, dynamic light scattering, and atomic force microscopy.
  • Assessed the impact of TTR on intracellular calcium ([Ca(2+)](i)) concentrations in SH-SY5Y human neuroblastoma cells.
  • Investigated the source of calcium influx, focusing on voltage-gated calcium channels (VGCCs).

Main Results:

  • Amyloidogenic TTR undergoes nucleation-dependent polymerization, forming oligomers before mature fibrils.
  • TTR rapidly increased [Ca(2+)](i) in neuroblastoma cells, with oligomers showing the most significant effect.
  • TTR-induced calcium increase resulted from extracellular calcium influx, primarily through L- and N-type VGCCs.

Conclusions:

  • TTR oligomers, not mature fibrils, appear to be the primary cytotoxic form.
  • Disruption of calcium homeostasis via VGCCs is a key early event in TTR-induced neurotoxicity.
  • Understanding this mechanism may offer therapeutic targets for familial amyloidotic polyneuropathy.

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