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Transthyretin oligomers induce calcium influx via voltage‐gated calcium channels
Author(s) -
Hou Xu,
Parkington Helena C.,
Coleman Harold A.,
Mechler Adam,
Martin Lisandra L.,
Aguilar MarieIsabel,
Small David H.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04210.x
Subject(s) - transthyretin , chemistry , biophysics , calcium , extracellular , amyloid (mycology) , fibril , voltage dependent calcium channel , biochemistry , endocrinology , biology , inorganic chemistry , organic chemistry
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.