Screening for calcium channel modulators in CLN3 siRNA knock down SH-SY5Y neuroblastoma cells reveals a significant decrease of intracellular calcium levels by selected L-type calcium channel blockers

Biochim Biophys Acta. 2011 Feb;1810(2):186-91. doi: 10.1016/j.bbagen.2010.09.004. Epub 2010 Oct 7.


Background: Defects of the CLN3 gene on chromosome 16p12.1 lead to the juvenile form of neuronal ceroid-lipofuscinosis (JNCL, Batten Disease), the most common recessive inherited neurodegenerative disorder in children. Dysregulation of intracellular calcium homeostasis in the absence of a functional CLN3 protein (CLN3P, Battenin) has been linked to synaptic dysfunction and accelerated apoptosis in vulnerable neuronal cells. Prolonged increase of intracellular calcium concentration is considered to be a significant trigger for neuronal apoptosis and cellular loss in JNCL.

Methods: We examined the potential effect of 41 different calcium channel modulators on intracellular calcium concentration in CLN3 siRNA knock down SH-SY5Y neuroblastoma cells.

Results: Six drugs belonging to the group of voltage dependent L-type channel blockers show significant lowering of the increased intracellular calcium levels in CLN3 siRNA knock down cells.

Conclusions: Our studies provide important new data suggesting possible beneficial effects of the tested drugs on calcium flux regulated pathways in neuronal cell death. Therapeutic intervention in this untreatable disease will likely require drugs that cross the blood-brain barrier as did all of the positively screened drugs in this study.

General significance: Better comprehension of the mechanism of neurodegeneration in rare recessive disorders, such as neuronal ceroid-lipofuscinoses, is likely to help to better understand mechanisms involved in more complex genetic neurodegenerative conditions, such as those associated with aging.

MeSH terms

  • 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / pharmacology
  • Amlodipine / pharmacology
  • Blotting, Western
  • Calcium / metabolism*
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels, L-Type / metabolism
  • Cell Line, Tumor
  • Child
  • Drug Evaluation, Preclinical
  • Flunarizine / pharmacology
  • Humans
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Membrane Glycoproteins / genetics*
  • Molecular Chaperones / genetics*
  • Neuroblastoma / genetics
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology
  • Neuronal Ceroid-Lipofuscinoses / genetics
  • Neuronal Ceroid-Lipofuscinoses / metabolism
  • Nicardipine / pharmacology
  • Nifedipine / pharmacology
  • Nimodipine / pharmacology
  • Potassium Chloride / pharmacology
  • RNA Interference
  • RNA, Small Interfering / genetics*


  • CLN3 protein, human
  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Membrane Glycoproteins
  • Molecular Chaperones
  • RNA, Small Interfering
  • Amlodipine
  • Nimodipine
  • Potassium Chloride
  • 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
  • Nicardipine
  • Nifedipine
  • Flunarizine
  • Calcium