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AMPA induced Ca2+ influx in motor neurons occurs through voltage gated Ca2+ channel and Ca2+ permeable AMPA receptor.
Neurochem Int. 2011 Nov; 59(6):913-21.NI

Abstract

The rise in intracellular Ca(2+) mediated by AMPA subtype of glutamate receptors has been implicated in the pathogenesis of motor neuron disease, but the exact route of Ca(2+) entry into motor neurons is not clearly known. In the present study, we examined the role of voltage gated calcium channels (VGCCs) in AMPA induced Ca(2+) influx and subsequent intracellular signaling events responsible for motor neuron degeneration. AMPA stimulation caused sodium influx in spinal neurons that would depolarize the plasma membrane. The AMPA induced [Ca(2+)](i) rise in motor neurons as well as other spinal neurons was drastically reduced when extracellular sodium was replaced with NMDG, suggesting the involvement of voltage gated calcium channels. AMPA mediated rise in [Ca(2+)](i) was significantly inhibited by L-type VGCC blocker nifedipine, whereas ω-agatoxin-IVA and ω-conotoxin-GVIA, specific blockers of P/Q type and N-type VGCC were not effective. 1-Napthyl-acetyl spermine (NAS), an antagonist of Ca(2+) permeable AMPA receptors partially inhibited the AMPA induced [Ca(2+)](i) rise but selectively in motor neurons. Measurement of AMPA induced currents in whole cell voltage clamp mode suggests that a moderate amount of Ca(2+) influx occurs through Ca(2+) permeable AMPA receptors in a subpopulation of motor neurons. The AMPA induced mitochondrial calcium loading [Ca(2+)](m), mitochondrial depolarization and neurotoxicity were also significantly reduced in presence of nifedipine. Activation of VGCCs by depolarizing concentration of KCl (30mM) in extracellular medium increased the [Ca(2+)](i) but no change was observed in mitochondrial Ca(2+) and membrane potential. Our results demonstrate that a subpopulation of motor neurons express Ca(2+) permeable AMPA receptors, however the larger part of Ca(2+) influx occurs through L-type VGCCs subsequent to AMPA receptor activation and consequent mitochondrial dysfunction is the trigger for motor neuron degeneration. Nifedipine is an effective protective agent against AMPA induced mitochondrial stress and degeneration of motor neurons.

Authors+Show Affiliations

Department of Biophysics, National Institute of Mental Health and Neuro Sciences, Bangalore 560 029, India.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

21777635

Citation

Joshi, Dinesh C., et al. "AMPA Induced Ca2+ Influx in Motor Neurons Occurs Through Voltage Gated Ca2+ Channel and Ca2+ Permeable AMPA Receptor." Neurochemistry International, vol. 59, no. 6, 2011, pp. 913-21.
Joshi DC, Singh M, Krishnamurthy K, et al. AMPA induced Ca2+ influx in motor neurons occurs through voltage gated Ca2+ channel and Ca2+ permeable AMPA receptor. Neurochem Int. 2011;59(6):913-21.
Joshi, D. C., Singh, M., Krishnamurthy, K., Joshi, P. G., & Joshi, N. B. (2011). AMPA induced Ca2+ influx in motor neurons occurs through voltage gated Ca2+ channel and Ca2+ permeable AMPA receptor. Neurochemistry International, 59(6), 913-21. https://doi.org/10.1016/j.neuint.2011.06.023
Joshi DC, et al. AMPA Induced Ca2+ Influx in Motor Neurons Occurs Through Voltage Gated Ca2+ Channel and Ca2+ Permeable AMPA Receptor. Neurochem Int. 2011;59(6):913-21. PubMed PMID: 21777635.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - AMPA induced Ca2+ influx in motor neurons occurs through voltage gated Ca2+ channel and Ca2+ permeable AMPA receptor. AU - Joshi,Dinesh C, AU - Singh,Mahendra, AU - Krishnamurthy,Karthik, AU - Joshi,Preeti G, AU - Joshi,Nanda B, Y1 - 2011/07/13/ PY - 2011/03/22/received PY - 2011/06/27/revised PY - 2011/06/29/accepted PY - 2011/7/23/entrez PY - 2011/7/23/pubmed PY - 2013/1/30/medline SP - 913 EP - 21 JF - Neurochemistry international JO - Neurochem Int VL - 59 IS - 6 N2 - The rise in intracellular Ca(2+) mediated by AMPA subtype of glutamate receptors has been implicated in the pathogenesis of motor neuron disease, but the exact route of Ca(2+) entry into motor neurons is not clearly known. In the present study, we examined the role of voltage gated calcium channels (VGCCs) in AMPA induced Ca(2+) influx and subsequent intracellular signaling events responsible for motor neuron degeneration. AMPA stimulation caused sodium influx in spinal neurons that would depolarize the plasma membrane. The AMPA induced [Ca(2+)](i) rise in motor neurons as well as other spinal neurons was drastically reduced when extracellular sodium was replaced with NMDG, suggesting the involvement of voltage gated calcium channels. AMPA mediated rise in [Ca(2+)](i) was significantly inhibited by L-type VGCC blocker nifedipine, whereas ω-agatoxin-IVA and ω-conotoxin-GVIA, specific blockers of P/Q type and N-type VGCC were not effective. 1-Napthyl-acetyl spermine (NAS), an antagonist of Ca(2+) permeable AMPA receptors partially inhibited the AMPA induced [Ca(2+)](i) rise but selectively in motor neurons. Measurement of AMPA induced currents in whole cell voltage clamp mode suggests that a moderate amount of Ca(2+) influx occurs through Ca(2+) permeable AMPA receptors in a subpopulation of motor neurons. The AMPA induced mitochondrial calcium loading [Ca(2+)](m), mitochondrial depolarization and neurotoxicity were also significantly reduced in presence of nifedipine. Activation of VGCCs by depolarizing concentration of KCl (30mM) in extracellular medium increased the [Ca(2+)](i) but no change was observed in mitochondrial Ca(2+) and membrane potential. Our results demonstrate that a subpopulation of motor neurons express Ca(2+) permeable AMPA receptors, however the larger part of Ca(2+) influx occurs through L-type VGCCs subsequent to AMPA receptor activation and consequent mitochondrial dysfunction is the trigger for motor neuron degeneration. Nifedipine is an effective protective agent against AMPA induced mitochondrial stress and degeneration of motor neurons. SN - 1872-9754 UR - https://www.unboundmedicine.com/medline/citation/21777635/AMPA_induced_Ca2+_influx_in_motor_neurons_occurs_through_voltage_gated_Ca2+_channel_and_Ca2+_permeable_AMPA_receptor_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0197-0186(11)00230-0 DB - PRIME DP - Unbound Medicine ER -