Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95.
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.
Jo
Jihoon
J
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Faculty of Medicine and Dentistry, University of Bristol, Bristol, UK.
Son
Gi Hoon
GH
Winters
Bryony L
BL
Kim
Myung Jong
MJ
Whitcomb
Daniel J
DJ
Dickinson
Bryony A
BA
Lee
Youn-Bok
YB
Futai
Kensuke
K
Amici
Mascia
M
Sheng
Morgan
M
Collingridge
Graham L
GL
Cho
Kwangwook
K
D000109:Acetylcholine / Q000378:metabolism; D033962:Adaptor Protein Complex 2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001703:Biophysics / Q000379:methods; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D000076122:Disks Large Homolog 4 Protein; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology*; D051597:Hippocalcin / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D021381:Protein Transport / Q000502:physiology; D015363:Quinolones / Q000494:pharmacology; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D011976:Receptors, Muscarinic / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*; D020798:Two-Hybrid System Techniques
C531940:77-LH-28-1; D033962:Adaptor Protein Complex 2; D018679:Cholinergic Agonists; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D018683:Excitatory Amino Acid Agents; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018727:Muscarinic Antagonists; D010880:Piperidines; D015363:Quinolones; D011976:Receptors, Muscarinic; D016194:Receptors, N-Methyl-D-Aspartate; D051597:Hippocalcin; D002217:Carbachol; D000109:Acetylcholine; D002118:Calcium