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Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95.

Authors: Jo, Jihoon  Son, Gi Hoon  Winters, Bryony L  Kim, Myung Jong  Whitcomb, Daniel J  Dickinson, Bryony A  Lee, Youn-Bok  Futai, Kensuke  Amici, Mascia  Sheng, Morgan  Collingridge, Graham L  Cho, Kwangwook 
Citation: Jo J, etal., Nat Neurosci. 2010 Oct;13(10):1216-24. doi: 10.1038/nn.2636. Epub 2010 Sep 19.
Pubmed: (View Article at PubMed) PMID:20852624
DOI: Full-text: DOI:10.1038/nn.2636

Although muscarinic acetylcholine receptors (mAChRs) and NMDA receptors (NMDARs) are important for synaptic plasticity, learning and memory, the manner in which they interact is poorly understood. We found that stimulation of muscarinic receptors, either by an agonist or by the synaptic release of acetylcholine, led to long-term depression (LTD) of NMDAR-mediated synaptic transmission. This form of LTD involved the release of Ca2+ from IP3-sensitive intracellular stores and was expressed via the internalization of NMDARs. Our results suggest that the molecular mechanism involves a dynamic interaction between the neuronal calcium sensor protein hippocalcin, the clathrin adaptor molecule AP2, the postsynaptic density enriched protein PSD-95 and NMDARs. We propose that hippocalcin binds to the SH3 region of PSD-95 under basal conditions, but it translocates to the plasma membrane on sensing Ca2+; in doing so, it causes PSD-95 to dissociate from NMDARs, permitting AP2 to bind and initiate their dynamin-dependent endocytosis.

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CRRD Object Information
CRRD ID: 13702412
Created: 2018-07-18
Species: All species
Last Modified: 2018-07-18
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.