The role of metabotropic L-glutamate (mGlu) receptors in supralinear Ca 2ϩ signaling was investigated in cultured hippocampal cells using Ca 2ϩ imaging techniques and whole-cell voltageclamp recording. In neurons, but not glia, global supralinear Ca 2ϩ release from intracellular stores was observed when the mGlu receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) was combined with elevated extracellular K ϩ levels (10.8 mM), moderate depolarization (15-30 mV), or NMDA (3 M). There was a delay (2-8 min) before the stores were fully charged, and the enhancement persisted for a short period (up to 10 min) after removal of the store-loading stimulus. Studies with the mGlu receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine demonstrated that these effects were mediated by activation of the mGlu 5 receptor subtype. The L-type voltage-gated Ca 2ϩ channel antagonist nifedipine (10 M) substantially reduced responses to DHPG obtained in the presence of elevated extracellular K ϩ but not NMDA. This suggests that the Ca 2ϩ that is required to load the stores can enter either through L-type voltage-gated Ca 2ϩ channels or directly through NMDA receptors. The findings that both depolarization and NMDA receptor activation can facilitate mGlu receptor Ca 2ϩ signaling adds considerable flexibility to the processes that underlie activity-dependent changes in synaptic strength. In particular, a temporal separation between the store-loading stimulus and the activation of mGlu receptors could be used as a recency detector in neurons. Local and global elevations in neuronal cytosolic Ca 2ϩ are important for a variety of physiological and pathological processes, including synaptic plasticity and gene expression (Berridge, 1998). The role of NMDA receptors in hippocampal Ca 2ϩ signaling has been the subject of intense investigation (Mayer et al., 1987;Regehr and Tank, 1992;Segal and Manor, 1992;Alford et al., 1993;Perkel et al., 1993;Malinow et al., 1994;Petrozzino et al., 1995;Schiller et al., 1998;Emptage et al., 1999;Yuste et al., 1999;Kovalchuk et al., 2000), fueled by the role of these receptors in processes such as long-term potentiation (LTP) and long-term depression (LTD) (Bliss and Collingridge, 1993;Bear and Abraham, 1996). Of particular significance for hebbian plasticity, the biophysical properties of NMDA receptors enable them to act as coincidence detectors, whereby they only generate an effective response in the presence of a postsynaptic depolarization (Nowak et al., 1984;Mayer et al., 1984). These characteristics, coupled with their permeability to Ca 2ϩ (Jahr and Stevens, 1987;Mayer et al., 1987;Ascher and Nowak, 1988), make them ideally suited to converting changes in synaptic activity into intracellular Ca 2ϩ signals (Bliss and Collingridge, 1993).Recently, interest has grown in the possibility that metabotropic L-glutamate (mGlu) receptors could also act as coincidence detectors by generating supralinear Ca 2ϩ signals during membrane depolarization (Emptage, 1999;Nakamura et al., 1999). The physiological re...
