AMPA receptor activation induces association of G-beta protein with the alpha subunit of the sodium channel in neurons.
Glutamatergic transmission is mediated by ionotropic receptors that directly gate cationic channels and metabotropic receptors that are coupled to second messenger generating systems and to ionic channels via heterotrimeric guanine-nucleotide binding- (G) proteins. This distinction cannot be made for the ionotropic receptor subclass activated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), which has been shown to be physically associated with the alpha-subunit of Gi1 protein and activates this G-protein. Here, we report that, in addition to a Ca2+ influx, AMPA induces the mobilization of Ca2+ from the mitochondrial pool by reversing the mitochondrial Na+/Ca2+ exchanger in mouse neurons in primary culture. Both processes required the activation of tetrodotoxin-sensitive Na+ channels. AMPA receptor activation modified the gating properties of the Na+ channel, independently of the AMPA current, suggesting a G-protein-mediated process. Indeed, co-immunoprecipitation experiments indicated that AMPA receptor activation induced the association of Gbeta with the alpha-subunit of the Na+ channel. These results suggest that, in addition to its ionic channel function, the AMPA receptor is coupled to Na+ channels through G-proteins and that this novel metabotropic function is involved in the control of neuronal excitability.
Marin
P
P
INSERM U114, Collège de France, 11, Place Marcelin Berthelot, 75231 Paris Cedex 05, France.
Fagni
L
L
Torrens
Y
Y
Alcaraz
G
G
Couraud
F
F
Bockaert
J
J
Glowinski
J
J
Prémont
J
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005333:Fetus; D020962:Heterotrimeric GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D011247:Pregnancy; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; C568249:Scn1a protein, mouse; D015222:Sodium Channels; D019831:Sodium-Calcium Exchanger; D013779:Tetrodotoxin; D020962:Heterotrimeric GTP-Binding Proteins; D002118:Calcium