Metabotropic Glutamate Receptor-Mediated LTD Involves Two Interacting Ca²⁺ Sensors, NCS-1 and PICK1

There are two major forms of long-term depression (LTD) of synaptic transmission in the central nervous system that require activation of either N-methyl-D-aspartate receptors (NMDARs) or metabotropic glutamate receptors (mGluRs). In synapses in the perirhinal cortex, we have directly compared the Ca²⁺ signaling mechanisms involved in NMDAR-LTD and mGluR-LTD. While both forms of LTD involve Ca²⁺ release from intracellular stores, the Ca²⁺ sensors involved are different; NMDAR-LTD involves calmodulin, while mGluR-LTD involves the neuronal Ca²⁺ sensor (NCS) protein NCS-1. In addition, there is a specific requirement for IP3 and PKC, as well as protein interacting with C kinase (PICK-1) in mGluR-LTD. NCS-1 binds directly to PICK1 via its BAR domain in a Ca²⁺-dependent manner. Furthermore, the NCS-1-PICK1 association is stimulated by activation of mGluRs, but not NMDARs, and introduction of a PICK1 BAR domain fusion protein specifically blocks mGluR-LTD. Thus, NCS-1 plays a distinct role in mGluR-LTD.