mGluR1-mediated potentiation of NMDA receptors involves a rise in intracellular calcium and activation of protein kinase C

• Published in: Neuropharmacology 2001-06, Vol.40 (7), p.856-865
• Main Authors: Skeberdis, Vytenis A, Lan, Jian-yu, Opitz, Thoralf, Zheng, Xin, Bennett, Michael V.L, Zukin, R.Suzanne
• Format: Article
• Language: English
• Subjects: (1 S,3 R)-ACPD; Aminoacid receptors (glycine, glutamate, gaba); Animals; Biological and medical sciences; Calcium - metabolism; Cell receptors; Cell structures and functions; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Cycloleucine - analogs & derivatives; Cycloleucine - antagonists & inhibitors; Cycloleucine - pharmacology; Enzyme Inhibitors - pharmacology; Excitatory Amino Acid Agonists - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Metabotropic glutamate receptors; Mice; Molecular and cellular biology; N-Methyl- d-aspartate receptors; Phospholipase C; Protein kinase C; Protein Kinase C - drug effects; Protein Kinase C - metabolism; Rats; Receptors, Metabotropic Glutamate - drug effects; Receptors, Metabotropic Glutamate - metabolism; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - metabolism; Tetradecanoylphorbol Acetate - pharmacology; Vertebrates: nervous system and sense organs; Xenopus laevis; Xenopus oocytes
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/S0028-3908(01)00005-3

Potentiation of ionotropic glutamate receptor activity by metabotropic glutamate receptors (mGluRs) is thought to modulate activity at glutamatergic synapses in the hippocampus. However, the precise pathway by which this modulation occurs is not well understood. The present study tests the hypothesis that mGluR1-mediated potentiation of N-methyl- d-aspartate receptors (NMDARs) occurs via a phospholipase C (PLC)-initiated cascade. NMDAR functional activity was examined by whole-cell recording from Xenopus oocytes expressing recombinant NMDARs and mGluR1α. The mGluR1 agonist (1 S,3 R)-1-amino-cyclopentane-1,3-dicarboxylic acid (ACPD) significantly potentiated NMDA-elicited currents. mGluR1α-mediated potentiation of NMDA responses was eliminated by the PLC inhibitor U-73122. Buffering of intracellular Ca 2+ by BAPTA-AM or depletion of intracellular Ca 2+ by the Ca 2+/ATPase inhibitor thapsigargin 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 further potentiation after potentiation of NMDARs by the PKC-activating phorbol ester 12- O-tetradecanoyl phorbol-13-acetate (TPA). Thus, Group I mGluRs potentiate NMDA responses via activation of PLC; at least part of the potentiation is due to rise in intracellular Ca 2+ and stimulation of PKC. Cytochalasin D, which disrupts the actin cytoskeleton, blocked ACPD-elicited chloride currents and ACPD-induced potentiation of NMDAR currents, consistent with 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 may play a role in synaptic transmission and plasticity including LTP.