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

Jihoon Jo, Gi Hoon Son, Bryony L. Winters, Myung Jong Kim, Daniel J. Whitcomb, Bryony A. Dickinson, Youn Bok Lee, Kensuke Futai, Mascia Amici, Morgan Sheng, Graham L. Collingridge, Kwangwook Cho

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1216-1224
Number of pages9
JournalNature Neuroscience
Volume13
Issue number10
DOIs
Publication statusPublished - 2010 Oct 1
Externally publishedYes

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Hippocalcin
Muscarinic Receptors
N-Methyl-D-Aspartate Receptors
Neuronal Calcium-Sensor Proteins
Vesicular Transport Adaptor Proteins
Dynamins
Neuronal Plasticity
Endocytosis
Synaptic Transmission
Acetylcholine
Cell Membrane
Learning

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Jo, J., Son, G. H., Winters, B. L., Kim, M. J., Whitcomb, D. J., Dickinson, B. A., ... Cho, K. (2010). Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95. Nature Neuroscience, 13(10), 1216-1224. https://doi.org/10.1038/nn.2636

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

In: Nature Neuroscience, Vol. 13, No. 10, 01.10.2010, p. 1216-1224.

Research output: Contribution to journalArticle

Jo, J, Son, GH, Winters, BL, Kim, MJ, Whitcomb, DJ, Dickinson, BA, Lee, YB, Futai, K, Amici, M, Sheng, M, Collingridge, GL & Cho, K 2010, 'Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95', Nature Neuroscience, vol. 13, no. 10, pp. 1216-1224. https://doi.org/10.1038/nn.2636
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. / Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95. In: Nature Neuroscience. 2010 ; Vol. 13, No. 10. pp. 1216-1224.
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