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ToxSci Advance Access published online on November 4, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh004
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received August 1, 2003; accepted September 23, 2003
© 2003 Society of Toxicology

Neurotoxicology

Noncoplanar 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) Amplifies Ionotropic Glutamate Receptor Signaling in Embryonic Cerebellar Granule Neurons by a Mechanism Involving Ryanodine Receptors

Juliette Gafni 1, Patty W. Wong 1, and Isaac N. Pessah 1*

1 Department of Molecular Biosciences, University of California, Davis, CA 95616; Center for Children's Environmental Health and Disease Prevention, University of California, Davis, CA 95616

* To whom correspondence should be addressed. E-mail: inpessah{at}ucdavis.edu.


  Abstract

The mechanisms by which noncoplanar 2,2',3,5',6-pentachlorobiphenyl (PCB 95) and rapamycin interact with ryanodine receptor (RyR) complexes to alter Ca2+ signaling was explored in intact cerebellar granule neurons. PCB 95 (10 µM, 20 min) significantly increased the number of neurons responding to caffeine. PCB 95 sensitization of RyR-mediated responses was further supported by the observations that ryanodine pretreatment blocked response to caffeine and coplanar 2,4,4',5-tetrachlorobiphenyl (PCB 66), which lacks RyR activity, failed to sensitize neurons. PCB 95 did not significantly alter levels of resting cytosolic Ca2+ nor thapsigargin-sensitive Ca2+ stores, suggesting a more complex mechanism than sensitization from increased cytosolic Ca2+ or an increased endoplasmic reticulum/cytosolic Ca2+ gradient. The immunosuppressant, rapamycin, sensitized neurons to caffeine in amanner similar to PCB 95, suggesting a common mechanism. PCB 95 or rapamycin significantly enhanced Ca2+ responses following N-methyl-D-aspartate (NMDA) and {alpha}-amino-3-hydroxy-5-methyl-4-isoxasolepropiate (AMPA) receptor activation. Store depletion or direct block of RyR with ryanodine enhanced responses to NMDA. PCB 95 further enhanced these responses to NMDA. These results suggest that PCB 95 and rapamycin enhance NMDA and AMPA mediated Ca2+ signals by modifying a functional association of the FKBP12/RyR complex that results in amplification of glutamate signaling in cultured cerebellar granule neurons in culture.

Key Words: Polychlorinated biphenyls, cerebellar granule neurons, calcium signaling, glutamate excitotoxicity, ryanodine receptors .


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