Figure 2: Signalling mechanisms involved in mGluR-LTD(A).

A | Signalling mechanisms that are involved in metabotropic glutamate receptor (mGluR)-dependent, AMPAR-mediated long-term depression (LTD(A)) in the hippocampus. Aa | Stimulation of group I mGluRs (here, mGlu5) leads to activation of phosphoinositide-specific phospholipase C (PLC). This can trigger the release of Ca²⁺ from intracellular stores and the activation of protein kinase C (PKC). In some forms of mGluR-LTD, PICK1 may target PKCα to phosphorylate ser880 of GluA2 to displace AMPAR-binding protein and glutamate receptor interacting protein (ABP–GRIP) and permit the removal of AMPARs from synapses. GRIP may then be sequestered by microtubule associated protein 1B (MAP1B). NCS1 has been implicated as a Ca²⁺ sensor and as a targeting molecule that is involved in this cascade. Ab | Several lines of evidence implicate p38 mitogen-activated protein kinase (p38 MAPK) and, to a lesser extent, extracellular signal-regulated kinases (ERKs) in mGluR-LTD, however, the downstream effectors are largely unknown. Ac | Activation of protein tyrosine phosphatases (PTPs) is also required for mGluR-LTD. Although the identity of the PTPs that are involved has not been firmly established, one candidate is striatal-enriched protein phosphatase (STEP). Ad | Arc is also involved in mGluR-LTD and it may help to initiate dynamin-dependent endocytosis of AMPARs. Ae | In some studies mGluR-LTD has been shown to require rapid (in a few minutes) de novo protein synthesis, with Arc, MAP1B and STEP as candidate protein molecules and eukaryotic elongation factor-2 kinase (eEF2K/eEF2) as one of the putative regulators of translation. Af | There is also evidence that the phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamicin (mTOR) pathway may control translation during mGluR-LTD. B | Signalling mechanisms that are involved in mGluR-LTD(A) in the cerebellum. At parallel fibre synapses onto Purkinje cells in the cerebellum, a form of mGluR-LTD(A) that requires activation of mGlu1 receptors has been extensively characterized. There are several similarities between cerebellar mGluR-LTD(A) and hippocampal mGluR-LTD(A) but some striking differences have also been found. Most notably, this form of LTD involves Ca²⁺ entry through voltage-gated Ca²⁺ channels (VGCC) and there is a requirement for 'orphan' glutamate receptor delta 2 (GluD2) subunits. A role for the nitric oxide–cyclic guanosine monophosphate (NO–cGMP) cascade has also been identified. Ser/Thr phosphatases negatively regulate this form of LTD(A) (not shown). CaM, calmodulin; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; DAG, dyacylglycerol; IP3, inositol trisphosphate; IP3R, inositol trisphosphate receptor; PIKE, PI 3-kinase enhancer; PP1, protein phosphatase 1; PP2A, protein phosphatase 2A; PP2B, protein phosphatase 2B.