Caenorhabditis elegans glutamate transporter deletion induces AMPA-receptor/adenylyl cyclase 9-dependent excitotoxicity.
In stroke and several neurodegenerative diseases, malfunction of glutamate (Glu) transporters causes Glu accumulation and triggers excitotoxicity. Many details on the cascade of events in the neurodegenerative process remain unclear. As molecular components of glutamatergic synapses are assembled in Caenorhabditis elegans and as many fundamental cellular processes are conserved from nematodes to humans, we studied Glu-induced necrosis in C. elegans and probed its genetic requirements. We combined deltaglt-3, a Glu transporter-null mutation, with expression of a constitutively active form of the alpha subunit of the G protein Gs. While neither deltaglt-3 nor expression of the constitutively active form of the alpha subunit of the G protein Gs is severely toxic to C. elegans head interneurons, their combination induces extensive neurodegeneration. deltaglt-3-dependent neurodegeneration acts through Ca2+-permeable Glu receptors of the alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) subtype, requires calreticulin function, and is modulated by calcineurin and type-9 adenylyl cyclase (AC9). We further show that mammalian AC9 hyperactivates mammalian AMPA-receptors (AMPA-Rs) in a Xenopus oocyte expression system, supporting that the relationship between AMPA-Rs hyperactivation and AC9 might be conserved between nematodes and mammals. AMPA-Rs-AC9 synergism is thus critical for nematode excitotoxicity and could potentially be involved in some forms of mammalian neurodegeneration.
Mano
Itzhak
I
Department of Molecular Biology & Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA. imano@ccny.cuny.edu
Driscoll
Monica
M
D000262:Adenylyl Cyclases / Q000378:metabolism*; D027322:Amino Acid Transport System X-AG / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D019703:Calcineurin / Q000172:deficiency; D002154:Calpain / Q000172:deficiency; D037282:Calreticulin / Q000172:deficiency; D016923:Cell Death / Q000235:genetics; D002490:Central Nervous System / Q000166:cytology; D017353:Gene Deletion; D049452:Green Fluorescent Proteins / Q000235:genetics; D008564:Membrane Potentials / Q000502:physiology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D009865:Oocytes; D018091:Receptors, AMPA / Q000378:metabolism*; D014982:Xenopus laevis
D027322:Amino Acid Transport System X-AG; D029742:Caenorhabditis elegans Proteins; D037282:Calreticulin; D018091:Receptors, AMPA; D049452:Green Fluorescent Proteins; D019703:Calcineurin; D002154:Calpain; D000262:Adenylyl Cyclases