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TRPM8 and Nav1.8 sodium channels are required for transthyretin-induced calcium influx in growth cones of small-diameter TrkA-positive sensory neurons

DOI: 10.1186/1750-1326-6-19

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Abstract:

Levels of intracellular cytosolic calcium were monitored in dorsal root ganglion (DRG) neurons isolated from embryonic rats using the calcium-sensitive fluorescent indicator Fluo4. An amyloidogenic mutant form of TTR, L55P, induced calcium influx into the growth cones of DRG neurons, whereas wild-type TTR had no significant effect. Atomic force microscopy and dynamic light scattering studies confirmed that the L55P TTR contained oligomeric species of TTR. The effect of L55P TTR was decreased by blockers of voltage-gated calcium channels (VGCC), as well as by blockers of Nav1.8 voltage-gated sodium channels and transient receptor potential M8 (TRPM8) channels. siRNA knockdown of TRPM8 channels using three different TRPM8 siRNAs strongly inhibited calcium influx in DRG growth cones.These data suggest that activation of TRPM8 channels triggers the activation of Nav1.8 channels which leads to calcium influx through VGCC. We suggest that TTR-induced calcium influx into DRG neurons may contribute to the pathophysiology of FAP. Furthermore, we speculate that similar mechanisms may mediate the toxic effects of other amyloidogenic proteins such as the β-amyloid protein of Alzheimer's disease.Protein misfolding is a common feature of many neurodegenerative diseases. In some of these diseases, such as the synucleinopathies and the tauopathies, cytoplasmic proteins aggregate to form intracellular deposits. However, in the amyloidoses, which include Alzheimer's disease (AD), prion diseases and the British and Danish familial dementias, proteinaceous aggregates are observed extracellularly [1-4]. There is increasing evidence that the mechanism of neurotoxicity in these amyloidoses is similar and that it is the conformation of the aggregated protein, rather than its specific amino acid sequence which results in altered membrane permeability to calcium [5]. Therefore, studies on the mechanism of neurotoxicity in one disease may provide insights into the mechanisms involved in other

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