A novel mechanism of hippocampal LTD involving muscarinic receptor-triggered interactions between AMPARs, GRIP and liprin-alpha.
BACKGROUND
Long-term depression (LTD) in the hippocampus can be induced by activation of different types of G-protein coupled receptors, in particular metabotropic glutamate receptors (mGluRs) and muscarinic acetylcholine receptors (mAChRs). Since mGluRs and mAChRs activate the same G-proteins and isoforms of phospholipase C (PLC), it would be expected that these two forms of LTD utilise the same molecular mechanisms. However, we find a distinct mechanism of LTD involving GRIP and liprin-alpha.


RESULTS
Whilst both forms of LTD require activation of tyrosine phosphatases and involve internalisation of AMPARs, they use different molecular interactions. Specifically, mAChR-LTD, but not mGluR-LTD, is blocked by peptides that inhibit the binding of GRIP to the AMPA receptor subunit GluA2 and the binding of GRIP to liprin-alpha. Thus, different receptors that utilise the same G-proteins can regulate AMPAR trafficking and synaptic efficacy via distinct molecular mechanisms.


CONCLUSIONS
Our results suggest that mAChR-LTD selectively involves interactions between GRIP and liprin-alpha. These data indicate a novel mechanism of synaptic plasticity in which activation of M1 receptors results in AMPAR endocytosis, via a mechanism involving interactions between GluA2, GRIP and liprin-alpha.
Dickinson
Bryony A
BA
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (LINE), Faculty of Medicine and Dentistry, University of Bristol, Whitson Street, Bristol BS1 3NY, UK. b.dickinson@bristol.ac.uk
Jo
Jihoon
J
Seok
Heon
H
Son
Gi Hoon
GH
Whitcomb
Daniel J
DJ
Davies
Ceri H
CH
Sheng
Morgan
M
Collingridge
Graham L
GL
Cho
Kwangwook
K
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C491308:Grip1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C498298:PICK1 protein, rat; D018091:Receptors, AMPA; D011976:Receptors, Muscarinic; D016194:Receptors, N-Methyl-D-Aspartate; D002217:Carbachol; C104722:glutamate receptor ionotropic, AMPA 2