Figure 1: Signalling mechanisms involved in NMDAR-dependent LTD.
a | Calmodulin (CaM) detects Ca2+ (shown by graded purple clouds) that enters via NMDARs and this leads, through a Ser/Thr protein phosphatase cascade, to activation of protein phosphatase 1 (PP1) a key enzyme in synaptically-induced LTD. PP1 can dephosphorylate various targets, including ser845 on the AMPAR subunit GluA1 and ser295 of postsynaptic density protein 95 (PSD95). b | GluA2-containing AMPARs are stabilised at synapses by an interaction with N-ethylmaleimide-sensitive factor (NSF). The neuronal calcium sensor protein hippocalcin (HPC) is a high-affinity Ca2+ sensor that can target adaptor protein 2 (AP2) to GluA2 and therefore displace NSF and initiate clathrin-mediated endocytosis of AMPARs. Ras-related protein (RalA)-binding protein 1 (RalBP1) may also be involved in the NMDAR-dependent targeting of AP2, where it associates with RalA. c | In some circumstances, protein interacting with C kinase 1 (PICK1) may aid the NMDAR-dependent disassociation of AMPARs from AMPAR-binding protein–glutamate receptor interacting protein (ABP–GRIP), potentially via the targeted phosphorylation of ser880 of GluA2 by protein kinase Cα (PKCα). PICK1, by binding actin-related protein 2/3 (Arp2/3) and F-actin, also acts as a negative regulator of Arp2/3-mediated actin polymerization. d | NMDAR-LTD is associated with phosphorylation (by protein tyrosine kinases (PTKs)) of tyr876 of GluA2 and this may also aid the exchange of PICK1 for ABP–GRIP. e | Glycogen synthase kinase-3β (GSK3β) is required for NMDAR-LTD during which it can be activated by PP1. The upstream regulators of GSK3β (the phosphoinositide 3-kinase (PI3K)–Akt pathway) enable the direct regulation of LTD by LTP. The release of cytochrome c from the mitochondria may activate caspase-9 and caspase-3, which can cleave Akt, possibly resulting in GSK3β activation. AKAP, A-kinase anchor protein; ARAP, AMPAR-associated protein; I-1, inhibitor 1; PP2B, protein phosphatase 2B; RyR, ryanodine receptor.
