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 language | English |
|---|---|
| Pages (from-to) | 1216-1224 |
| Number of pages | 9 |
| Journal | Nature Neuroscience |
| Volume | 13 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 2010 Oct 1 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Neuroscience(all)
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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 journal › Article
}
TY - JOUR
T1 - Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95
AU - Jo, Jihoon
AU - Son, Gi Hoon
AU - Winters, Bryony L.
AU - Kim, Myung Jong
AU - Whitcomb, Daniel J.
AU - Dickinson, Bryony A.
AU - Lee, Youn Bok
AU - Futai, Kensuke
AU - Amici, Mascia
AU - Sheng, Morgan
AU - Collingridge, Graham L.
AU - Cho, Kwangwook
PY - 2010/10/1
Y1 - 2010/10/1
N2 - 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.
AB - 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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U2 - 10.1038/nn.2636
DO - 10.1038/nn.2636
M3 - Article
VL - 13
SP - 1216
EP - 1224
JO - Nature Neuroscience
JF - Nature Neuroscience
SN - 1097-6256
IS - 10
ER -