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Requirement of both NR3A and NR3B subunits for dominant negative properties on Ca2+ mobilization mediated by acquired N-methyl-D-aspartate receptor channels into mitochondria.
Neurochem Int. 2010 Dec; 57(7):730-7.NI

Abstract

Conventional N-methyl-D-aspartate (NMDA) receptor (NMDAR) is a heteromeric complex between the essential NR1 subunit and one of NR2A-D subunits toward functional channels permeable to Ca(2+) rather than Na(+) ions. Although recent studies identified dominant negative NR3A and NR3B subunits, whether these subunits inhibit Ca(2+) mobilization through NMDAR channels into mitochondria is not clarified so far. In this study, we investigated Ca(2+) influx across acquired NMDAR channels composed of different NR subunits artificially expressed in HEK293 cells. The addition of NMDA markedly increased intracellular free Ca(2+) levels determined by Fluo-3 in cells transfected with either NR2A or NR2B subunit together with NR1 subunit. Further addition of dizocilpine completely inhibited the increase by NMDA in both types of acquired channels, while the NR2B subunit selective antagonist ifenprodil drastically inhibited the increase by NMDA in cells expressing NR1/NR2B, but not NR1/NR2A, subunits. Similar pharmacological profiles were invariably seen with cell death by NMDA. Introduction of both NR3A and NR3B subunits significantly inhibited the increase by NMDA in intracellular free Ca(2+) levels in both acquired channels, while introduction of either NR3A or NR3B alone was ineffective. Co-expression of both NR3A and NR3B subunits was also required for the prevention of increased mitochondrial free Ca(2+) levels determined by Rhod-2, as well as decreased cellular viability, in cells expressing NR1/NR2A or NR1/NR2B subunits upon exposure to NMDA. These results suggest that co-expression of both NR3A and NR3B subunits is essential for the dominant negative properties on Ca(2+) mobilization through acquired functional NMDAR channels into mitochondria.

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Authors+Show Affiliations

Fukumori R
Division of Pharmaceutical Sciences, Kanazawa University Graduate School of Natural Science and Technology, Kanazawa, Ishikawa, Japan.
Takarada T
No affiliation info available
Nakamichi N
No affiliation info available
Kambe Y
No affiliation info available
Kawagoe H
No affiliation info available
Nakazato R
No affiliation info available
Yoneda Y
No affiliation info available

MeSH

AnimalsCalciumCell SurvivalHEK293 CellsHumansMitochondriaN-MethylaspartateProtein SubunitsRatsReceptors, N-Methyl-D-Aspartate

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20813147

Citation

Fukumori, Ryo, et al. "Requirement of Both NR3A and NR3B Subunits for Dominant Negative Properties On Ca2+ Mobilization Mediated By Acquired N-methyl-D-aspartate Receptor Channels Into Mitochondria." Neurochemistry International, vol. 57, no. 7, 2010, pp. 730-7.
Fukumori R, Takarada T, Nakamichi N, et al. Requirement of both NR3A and NR3B subunits for dominant negative properties on Ca2+ mobilization mediated by acquired N-methyl-D-aspartate receptor channels into mitochondria. Neurochem Int. 2010;57(7):730-7.
Fukumori, R., Takarada, T., Nakamichi, N., Kambe, Y., Kawagoe, H., Nakazato, R., & Yoneda, Y. (2010). Requirement of both NR3A and NR3B subunits for dominant negative properties on Ca2+ mobilization mediated by acquired N-methyl-D-aspartate receptor channels into mitochondria. Neurochemistry International, 57(7), 730-7. https://doi.org/10.1016/j.neuint.2010.08.009
Fukumori R, et al. Requirement of Both NR3A and NR3B Subunits for Dominant Negative Properties On Ca2+ Mobilization Mediated By Acquired N-methyl-D-aspartate Receptor Channels Into Mitochondria. Neurochem Int. 2010;57(7):730-7. PubMed PMID: 20813147.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Requirement of both NR3A and NR3B subunits for dominant negative properties on Ca2+ mobilization mediated by acquired N-methyl-D-aspartate receptor channels into mitochondria. AU - Fukumori,Ryo, AU - Takarada,Takeshi, AU - Nakamichi,Noritaka, AU - Kambe,Yuki, AU - Kawagoe,Hirofumi, AU - Nakazato,Ryota, AU - Yoneda,Yukio, Y1 - 2010/09/08/ PY - 2010/04/30/received PY - 2010/07/21/revised PY - 2010/08/20/accepted PY - 2010/9/4/entrez PY - 2010/9/4/pubmed PY - 2011/9/8/medline SP - 730 EP - 7 JF - Neurochemistry international JO - Neurochem Int VL - 57 IS - 7 N2 - Conventional N-methyl-D-aspartate (NMDA) receptor (NMDAR) is a heteromeric complex between the essential NR1 subunit and one of NR2A-D subunits toward functional channels permeable to Ca(2+) rather than Na(+) ions. Although recent studies identified dominant negative NR3A and NR3B subunits, whether these subunits inhibit Ca(2+) mobilization through NMDAR channels into mitochondria is not clarified so far. In this study, we investigated Ca(2+) influx across acquired NMDAR channels composed of different NR subunits artificially expressed in HEK293 cells. The addition of NMDA markedly increased intracellular free Ca(2+) levels determined by Fluo-3 in cells transfected with either NR2A or NR2B subunit together with NR1 subunit. Further addition of dizocilpine completely inhibited the increase by NMDA in both types of acquired channels, while the NR2B subunit selective antagonist ifenprodil drastically inhibited the increase by NMDA in cells expressing NR1/NR2B, but not NR1/NR2A, subunits. Similar pharmacological profiles were invariably seen with cell death by NMDA. Introduction of both NR3A and NR3B subunits significantly inhibited the increase by NMDA in intracellular free Ca(2+) levels in both acquired channels, while introduction of either NR3A or NR3B alone was ineffective. Co-expression of both NR3A and NR3B subunits was also required for the prevention of increased mitochondrial free Ca(2+) levels determined by Rhod-2, as well as decreased cellular viability, in cells expressing NR1/NR2A or NR1/NR2B subunits upon exposure to NMDA. These results suggest that co-expression of both NR3A and NR3B subunits is essential for the dominant negative properties on Ca(2+) mobilization through acquired functional NMDAR channels into mitochondria. SN - 1872-9754 UR - https://www.unboundmedicine.com/medline/citation/20813147/Requirement_of_both_NR3A_and_NR3B_subunits_for_dominant_negative_properties_on_Ca2+_mobilization_mediated_by_acquired_N_methyl_D_aspartate_receptor_channels_into_mitochondria_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0197-0186(10)00264-0 DB - PRIME DP - Unbound Medicine ER -