PT - JOURNAL ARTICLE AU - Franca Codazzi AU - Alessandra Di Cesare AU - Nino Chiulli AU - Alberto Albanese AU - Tobias Meyer AU - Daniele Zacchetti AU - Fabio Grohovaz TI - Synergistic Control of Protein Kinase Cγ Activity by Ionotropic and Metabotropic Glutamate Receptor Inputs in Hippocampal Neurons AID - 10.1523/JNEUROSCI.0478-06.2006 DP - 2006 Mar 29 TA - The Journal of Neuroscience PG - 3404--3411 VI - 26 IP - 13 4099 - http://www.jneurosci.org/content/26/13/3404.short 4100 - http://www.jneurosci.org/content/26/13/3404.full SO - J. Neurosci.2006 Mar 29; 26 AB - Conventional protein kinase C (PKC) isoforms are abundant neuronal signaling proteins with important roles in regulating synaptic plasticity and other neuronal processes. Here, we investigate the role of ionotropic and metabotropic glutamate receptor (iGluR and mGluR, respectively) activation on the generation of Ca2+ and diacylglycerol (DAG) signals and the subsequent activation of the neuron-specific PKCγ isoform in hippocampal neurons. By combining Ca2+ imaging with total internal reflection microscopy analysis of specific biosensors, we show that elevation of both Ca2+ and DAG is necessary for sustained translocation and activation of EGFP (enhanced green fluorescent protein)-PKCγ. Both DAG production and PKCγ translocation were localized processes, typically observed within discrete microdomains along the dendritic branches. Markedly, intermediate-strength NMDA receptor (NMDAR) activation or moderate electrical stimulation generated Ca2+ but no DAG signals, whereas mGluR activation generated DAG but no Ca2+ signals. Both receptors were needed for PKCγ activation. This suggests that a coincidence detection process exists between iGluRs and mGluRs that relies on a molecular coincidence detection process based on the corequirement of Ca2+ and DAG for PKCγ activation. Nevertheless, the requirement for costimulation with mGluRs could be overcome for maximal NMDAR stimulation through a direct production of DAG via activation of the Ca2+-sensitive PLCδ (phospholipase Cδ) isoform. In a second important exception, mGluRs were sufficient for PKCγ activation in neurons in which Ca2+ stores were loaded by previous electrical activity. Together, the dual activation requirement for PKCγ provides a plausible molecular interpretation for different synergistic contributions of mGluRs to long-term potentiation and other synaptic plasticity processes.