Calpain inhibition reduces NMDA receptor rundown in rat substantia nigra dopamine neurons.
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Zhao, J., Baudry, M., & Jones, S. (2018). Calpain inhibition reduces NMDA receptor rundown in rat substantia nigra dopamine neurons.. Neuropharmacology, 137 221-229. https://doi.org/10.1016/j.neuropharm.2018.05.003
Abstract Repeated activation of N-Methyl-D-aspartate receptors (NMDARs) causes a Ca2+-dependent reduction in NMDAR-mediated current in dopamine (DA) neurons of the substantia nigra pars compacta (SNc) in one week old rats; however, a Ca2+-dependent regulatory protein has not been identified. The role of the Ca2+-dependent cysteine protease, calpain, in mediating NMDAR current rundown was investigated. In brain slices from rats aged postnatal day 7-9 (‘P7’), bath application of either of the membrane permeable calpain inhibitors, N-Acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN, 20 M) or MDL-28170 (30 M) significantly reduced whole-cell NMDAR current rundown. To investigate the role of the calpain-2 isoform, the membrane permeable calpain-2 inhibitor, Z-Leu-Abu-CONH-CH2-C6H3 (3, 5-(OMe)2 (C2I, 200 nM), was applied; C2I application significantly reduced whole cell NMDAR current rundown. Interestingly, ALLN but not C2I significantly reduced rundown of NMDA-EPSCs. These results suggest the calpain-2 isoform mediates Ca2+-dependent regulation of extrasynaptic NMDAR current in the first postnatal week, while calpain-1 might mediate rundown of synaptic NMDAR currents. One week later in postnatal development, at P12-P16 (‘P14’), there was significantly less rundown in SNc-DA neurons, and no significant effect on rundown of either Ca2+ chelation or treatment with the calpain inhibitor, ALLN, suggesting that the rundown observed in SNc-DA neurons from two week-old rats might be Ca2+-independent. In conclusion, Ca2+-dependent rundown of extrasynaptic NMDAR currents in SNc DA neurons involves calpain-2 activation, but Ca2+- and calpain-2-dependent NMDAR current rundown is developmentally regulated.
Synapses, Animals, Rats, Wistar, Cations, Divalent, Calcium, Calpain, Glycoproteins, Receptors, N-Methyl-D-Aspartate, Tissue Culture Techniques, Membrane Potentials, Membrane Transport Modulators, Dopaminergic Neurons, Pars Compacta
External DOI: https://doi.org/10.1016/j.neuropharm.2018.05.003
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279262
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Licence URL: http://creativecommons.org/licenses/by-nc-nd/4.0/