Va. Skeberdis et al., mGluR1-mediated potentiation of NMDA receptors involves a rise in intracellular calcium and activation of protein kinase C, NEUROPHARM, 40(7), 2001, pp. 856-865
Potentiation of ionotropic glutamate receptor activity by metabotropic glut
amate receptors (mGluRs) is thought to modulate activity at glutamatergic s
ynapses in the hippocampus. However, the precise pathway by which this modu
lation occurs is not well understood. The present study tests the hypothesi
s that mGluR1-mediated potentiation of N-methyl-D-aspartate receptors (NMDA
Rs) occurs via a phospholipase C (PLC)-initiated cascade. NMDAR functional
activity was examined by whole-cell recording from Xenopus oocytes expressi
ng recombinant NMDARs and mGluR1 alpha. The mGluR1 agonist(1S,3R)-1-amino-c
yclopentane-1,3-dicarboxylic acid (ACPD) significantly potentiated NMDA-eli
cited currents. mGluR1 alpha -mediated potentiation of NMDA responses was e
liminated by the PLC inhibitor U-73122. Buffering of intracellular Ca2+ by
BAPTA-AM or depletion of intracellular Ca2+ by the Ca2+/ATPase inhibitor th
apsigargin greatly reduced ACPD potentiation. ACPD potentiation was reduced
by the specific protein kinase C (PKC) inhibitor Ro-32-0432 and eliminated
by the broad spectrum kinase inhibitor staurosporine. ACPD produced no fur
ther potentiation after potentiation of NMDARs by the PKC-activating phorbo
l ester 12-O-tetradecanoyl phorbol-13-acetate (TPA). Thus, Group I mGluRs p
otentiate NMDA responses via activation of PLC; at least part of the potent
iation is due to rise in intracellular Ca2+ and stimulation of PKC. Cytocha
lasin D, which disrupts the actin cytoskeleton, blocked ACPD-elicited chlor
ide currents and ACPD-induced potentiation of NMDAR currents, consistent wi
th a role for cytoskeletal protein(s) in the signaling pathway. As Group I
mGluRs are localized to the perisynaptic region in juxtaposition to NMDARs
at glutamatergic synapses, mGluR-mediated potentiation of NMDAR activity ma
y play a role in synaptic transmission and plasticity including LTP. (C) 20
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