Metabotropic glutamate receptor subtype 1 regulates sodium currents in rat neocortical pyramidal neurons.
Brain sodium channels (NaChs) are regulated by various neurotransmitters such as acetylcholine, serotonin and dopamine. However, it is not known whether NaCh activity is regulated by glutamate, the principal brain neurotransmitter. We show here that activation of metabotropic glutamate receptor (mGluR) subtype 1 regulates fast transient (I(NaT)) and persistent Na(+) currents (I(NaP)) in cortical pyramidal neurons. A selective agonist of group I mGluR, (S)-3,5-dihydroxyphenylglycine (DHPG), reduced action potential amplitude and decreased I(NaT). This reduction was blocked when DHPG was applied in the presence of selective mGluR1 antagonists. The DHPG-induced reduction of the current was accompanied by a shift of both the inactivation curve of I(NaT) and the activation curve of I(NaP). These effects were dependent on the activation of PKC. The respective role of these two regulatory processes on neuronal excitability was determined by simulating transient and persistent Na(+) conductances (G(NaT) and G(NaP)) with fast dynamic-clamp techniques. The facilitated activation of G(NaP) increased excitability near the threshold, but, when combined with the down-regulation of G(NaT), repetitive firing was strongly decreased. Consistent with this finding, the mGluR1 antagonist LY367385 increased neuronal excitability when glutamatergic synaptic activity was stimulated with high external K(+). We conclude that mGluR1-dependent regulation of Na(+) current depresses neuronal excitability, which thus might constitute a novel mechanism of homeostatic regulation acting during intense glutamatergic synaptic activity.
Carlier
Edmond
E
INSERM U641, Marseille, F-13916 France.
Sourdet
Valérie
V
Boudkkazi
Sami
S
Déglise
Patrice
P
Ankri
Norbert
N
Fronzaroli-Molinieres
Laure
L
Debanne
Dominique
D
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D015640:Ion Channel Gating / Q000502:physiology*; D019579:Neocortex / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000502:physiology*
D018094:Receptors, Metabotropic Glutamate; D015222:Sodium Channels; C104077:metabotropic glutamate receptor type 1; D012964:Sodium