Complex influence of the L-type calcium-channel agonist BayK8644(+/-) on N-methyl-D-aspartate responses and neuronal survival

Neuroscience. 1999 Mar;89(1):101-8. doi: 10.1016/s0306-4522(98)00312-1.


Past studies have implicated calcium influx through the N-methyl-D-aspartate class of ionotropic glutamate receptors as a key factor in excitotoxicity. Here, primary cultures of hippocampal neurons were exposed to N-methyl-D-aspartate with or without the L-type calcium channel agonist BayK8644(+/-). Calcium influxes were monitored with Fura-2 microfluorescent imaging and 45Ca measurements, and survival was assayed through cell counts. While 100 microM BayK8644 alone evoked a moderate elevation of intraneuronal calcium concentrations ([Ca2+]i), it dramatically attenuated the larger calcium influxes triggered by 500 microM N-methyl-D-aspartate. This attenuation was non-competitive and reversible; it was not inhibited by charybdotoxin or cyclosporin A. In spite of this attenuation of [Ca2+]i responses, 5-min exposures to BayK8644 produced much greater neurotoxicity 24 h later than did doses of N-methyl-D-aspartate evoking larger [Ca2+]i increases. This neurotoxicity was not observed with potassium-mediated depolarization or cobalt; indeed, both reversed the neurotoxicity of BayK8644. The relevant conclusions are two-fold: BayK8644 inhibits influx of calcium through a ligand-gated glutamate receptor, and BayK8644 exhibits considerable neurotoxicity. The former effect does not appear to depend upon the major metabolic pathways that modulate N-methyl-D-aspartate channels and thus may involve a direct allosteric interaction with the N-methyl-D-aspartate receptor. The toxicity of BayK8644 depends, at least partially, upon its activation of voltage-gated (cobalt-sensitive) calcium channels. However, the reversal of this toxicity by depolarization suggests that depolarization can be beneficial to neuronal survival through mechanisms other than calcium influx through voltage-gated calcium channels.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / pharmacology*
  • Animals
  • Calcium Channel Agonists / pharmacology*
  • Calcium Channels / physiology*
  • Calcium Channels, L-Type
  • Cell Survival / drug effects
  • Charybdotoxin / pharmacology
  • Electric Stimulation
  • Electrophysiology
  • Excitatory Amino Acid Agonists / pharmacology*
  • Female
  • Fluorescent Dyes
  • Fura-2
  • Hippocampus / cytology
  • Ion Channel Gating / physiology
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • N-Methylaspartate / pharmacology*
  • Neurons / chemistry*
  • Neurons / drug effects
  • Neurotoxins / pharmacology
  • Potassium / pharmacology
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley


  • Calcium Channel Agonists
  • Calcium Channels
  • Calcium Channels, L-Type
  • Excitatory Amino Acid Agonists
  • Fluorescent Dyes
  • Neurotoxins
  • Charybdotoxin
  • N-Methylaspartate
  • 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
  • Potassium
  • Fura-2