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Ionotropic Receptors in the Central Nervous System and Neurodegenerative Disease

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Handbook of Neurotoxicity

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Abstract

Glutamate was identified as the main excitatory neurotransmitter in the mammalian central nervous system (CNS), following the observation in the early 1950s that glutamate can induce seizure activity and excite neurons in the mammalian brain. Over the last two decades, selective ligands, including competitive agonists and antagonists and allosteric modulators, have been developed to further investigate the functional role of glutaminergic receptors. Glutamate released from synapses can activate ligand-gated cation channels at postsynaptic cells to mediate fast postsynaptic potentials. These ion channel-forming ionotropic glutamate receptors (iGluRs) are divided into N-methyl-D-aspartate (NMDA), α-amino-3-hydroxyl-5-methyl-isoxazole-4-prorionate (AMPA), and kainate (KA) receptors. While only 20–30% of the amino acid sequence is shared among these receptor subtypes, they share similar structural features and their activity is based on specific pharmacological preference. In this chapter, the structure and composition of iGluRs will be described and their pharmacology inferred, with a particular focus on their role in the CNS and their relevance to the pathogenesis of neurodegenerative diseases.

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Abbreviations

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MPP+:

1-Methyl-4-phenylpyridinium ion

ALS:

Amyotrophic Lateral Sclerosis

AD:

Alzheimer’s disease

AMPA:

α-Amino-3-hydroxyl-5-methyl-isoxazole-4-prorionate

CNS:

Central nervous system

HD:

Huntington’s disease

iGluRs:

Ionotropic glutamate receptors

KA:

Kainate receptors

KP:

Kynurenine pathway

NAD+:

Nicotinamide adenine dinucleotide

NMDA:

N-methyl-D-aspartate

PD:

Parkinson’s disease

QUIN:

Quinolinic acid

TM I:

Transmembrane domain-1

TM II:

Transmembrane domain-2

TM III:

Transmembrane domain-3

TM IV:

Transmembrane domain-4

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Acknowledgments

This work was supported by the NHMRC Capacity Building Grant to Prof Perminder Sachdev. Nady Braidy is the recipient of an Alzheimer’s Australia Viertel Foundation Postdoctoral Research Fellowship at the University of New South Wales. The authors sincerely thank the Rebecca Cooper Medical Research Foundation for ongoing financial support of their research.

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Authors and Affiliations

  1. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia

    Tharusha Jayasena & Perminder Sachdev

  2. Neuropharmacology Group, MND and Neurodegenerative Diseases Research Centre, Macquarie University, Sydney, NSW, Australia

    Anne Poljak & Gilles J. Guillemin

  3. Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, NSW, Australia

    Anne Poljak

  4. Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, NSW, Australia

    Perminder Sachdev

  5. Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

    Nady Braidy

  6. School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

    Anne Poljak

  7. Neuroinflammation Group, Faculty of Medicine and Health Sciences, Macquarie University, Macquarie Park, NSW, Australia

    Gilles J. Guillemin

  8. School of Medical Sciences, Department of Pharmacology, Faculty of Medicine, University of NSW, Sydney, NSW, Australia

    Gilles J. Guillemin

  9. St Vincent’s Centre for Applied Medical Research, St Vincent’s Hospital, Sydney, NSW, Australia

    Gilles J. Guillemin

Authors
  1. Nady Braidy
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  2. Anne Poljak
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  3. Tharusha Jayasena
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  4. Gilles J. Guillemin
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  5. Perminder Sachdev
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Corresponding author

Correspondence to Nady Braidy .

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Editors and Affiliations

  1. Department of Biomedical Sciences, Quillen College of Medicine East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Braidy, N., Poljak, A., Jayasena, T., Guillemin, G.J., Sachdev, P. (2022). Ionotropic Receptors in the Central Nervous System and Neurodegenerative Disease. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-031-15080-7_126

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