The role of group I metabotropic glutamate receptors in neuronal excitotoxicity in Alzheimer's disease.
Neurodegenerative diseases such as Huntington's disease, ischemia, and Alzheimer's disease (AD) are major causes of death. Recently, metabotropic glutamate receptors (mGluRs), a group of seven-transmembrane-domain proteins that couple to G-proteins, have become of interest for studies of pathogenesis. Group I mGluRs control the levels of second messengers such as inositol 1,4,5-triphosphate (IP3), Ca2+ ions and cAMP. They elicit the release of arachidonic acid via intracellular Ca2+ mobilization from intracellular stores such as mitochondria and endoplasmic reticulum. This facilitates the release of glutamate and could trigger the formation of neurofibrillary tangles, a pathological hallmark of AD. mGluRs regulate neuronal injury and survival, possibly through a series of downstream protein kinase and cysteine protease signaling pathways that affect mitochondrially mediated programmed cell death. They may also play a role in glutamate-induced neuronal death by facilitating Ca(II) mobilization. Hence, mGluRs have become a target for neuroprotective drug development. They represent a pharmacological path to a relatively subtle amelioration of neurotoxicity because they serve a modulatory rather than a direct role in excitatory glutamatergic transmission.
Tsai
Vicky W-W
VW
School of Molecular and Microbial Sciences and Institute for Molecular Bioscience, University of Queensland, Brisbane 4072 Australia.
Scott
Heather L
HL
Lewis
Richard J
RJ
Dodd
Peter R
PR
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D018683:Excitatory Amino Acid Agents / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*
D018683:Excitatory Amino Acid Agents; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1