Editing AMPA receptor (section)

====LTD-induced endocytosis of AMPA receptors====
[[Image:AMPAReceptorEndocytosis.jpg|thumb|x200px|alt=LTD-Induced AMPA Receptor Endocytosis|LTD-induced endocytosis of AMPA receptors]]
[[Long-term depression]] enacts mechanisms to decrease AMPA receptor density in selected dendritic spines, dependent on [[clathrin]] and [[calcineurin]] and distinct from that of constitutive AMPAR trafficking.  The starting signal for AMPAR [[endocytosis]] is an NMDAR-dependent calcium influx from low-frequency stimulation, which in turn activates protein phosphatases [[PP1]] and calcineurin.  However, AMPAR endocytosis has also been activated by [[VDCC|voltage-dependent calcium channels]], agonism of AMPA receptors, and administration of [[insulin]], suggesting general calcium influx as the cause of AMPAR endocytosis.<ref name="Carroll et al.">{{cite journal | vauthors = Carroll RC, Beattie EC, Xia H, Lüscher C, Altschuler Y, Nicoll RA, Malenka RC, von Zastrow M | display-authors = 6 | title = Dynamin-dependent endocytosis of ionotropic glutamate receptors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 24 | pages = 14112–7 | date = November 1999 | pmid = 10570207 | pmc = 24199 | doi = 10.1073/pnas.96.24.14112 | bibcode = 1999PNAS...9614112C | doi-access = free }}</ref>  Blockage of PP1 did not prevent AMPAR endocytosis, but antagonist application to calcineurin led to significant inhibition of this process.<ref name="Beattie et al.">{{cite journal | vauthors = Beattie EC, Carroll RC, Yu X, Morishita W, Yasuda H, von Zastrow M, Malenka RC | title = Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD | journal = Nature Neuroscience | volume = 3 | issue = 12 | pages = 1291–300 | date = December 2000 | pmid = 11100150 | doi = 10.1038/81823 | doi-access = free }}</ref>

Calcineurin interacts with an endocytotic complex at the postsynaptic zone, explaining its effects on LTD.<ref name="Lai et al.">{{cite journal | vauthors = Lai MM, Hong JJ, Ruggiero AM, Burnett PE, Slepnev VI, De Camilli P, Snyder SH | title = The calcineurin-dynamin 1 complex as a calcium sensor for synaptic vesicle endocytosis | journal = The Journal of Biological Chemistry | volume = 274 | issue = 37 | pages = 25963–6 | date = September 1999 | pmid = 10473536 | doi = 10.1074/jbc.274.37.25963 | doi-access = free }}</ref>  The complex, consisting of a clathrin-coated pit underneath a section of AMPAR-containing plasma membrane and interacting proteins, is the direct mechanism for reduction of AMPARs, in particular GluR2/GluR3 subunit-containing receptors, in the synapse.  Interactions from calcineurin activate [[dynamin]] GTPase activity, allowing the clathrin pit to excise itself from the cell membrane and become a cytoplasmic vesicle.<ref name="pmid17547698">{{cite journal | vauthors = Jung N, Haucke V | title = Clathrin-mediated endocytosis at synapses | journal = Traffic | volume = 8 | issue = 9 | pages = 1129–36 | date = September 2007 | pmid = 17547698 | doi = 10.1111/j.1600-0854.2007.00595.x | doi-access = free }}</ref>  Once the clathrin coat detaches, other proteins can interact directly with the AMPARs using [[PDZ domain|PDZ]] carboxyl tail domains; for example, glutamate receptor-interacting protein 1 ([[GRIP1 (gene)|GRIP1]]) has been implicated in intracellular sequestration of AMPARs.<ref name="Daw et al.">{{cite journal | vauthors = Daw MI, Chittajallu R, Bortolotto ZA, Dev KK, Duprat F, Henley JM, Collingridge GL, Isaac JT | display-authors = 6 | title = PDZ proteins interacting with C-terminal GluR2/3 are involved in a PKC-dependent regulation of AMPA receptors at hippocampal synapses | journal = Neuron | volume = 28 | issue = 3 | pages = 873–86 | date = December 2000 | pmid = 11163273 | doi = 10.1016/S0896-6273(00)00160-4 | hdl = 2262/89240 | s2cid = 13727678 | hdl-access = free }}</ref>  Intracellular AMPARs are subsequently sorted for degradation by lysosomes or recycling to the cell membrane.<ref name="Ehlers et al.">{{cite journal | vauthors = Ehlers MD | title = Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting | journal = Neuron | volume = 28 | issue = 2 | pages = 511–25 | date = November 2000 | pmid = 11144360 | doi = 10.1016/S0896-6273(00)00129-X | s2cid = 16333109 | doi-access = free }}</ref>  For the latter, [[PICK1]] and PKC can displace GRIP1 to return AMPARs to the surface, reversing the effects of endocytosis and LTD. when appropriate.<ref name="pmid16055064">{{cite journal | vauthors = Lu W, Ziff EB | title = PICK1 interacts with ABP/GRIP to regulate AMPA receptor trafficking | journal = Neuron | volume = 47 | issue = 3 | pages = 407–21 | date = August 2005 | pmid = 16055064 | doi = 10.1016/j.neuron.2005.07.006 | s2cid = 17100359 | doi-access = free }}</ref>  Nevertheless, the highlighted calcium-dependent, dynamin-mediated mechanism above has been implicated as a key component of LTD. and as such may have applications to further behavioral research.<ref name="Yang et al.">{{cite journal | vauthors = Wang YT | title = Probing the role of AMPAR endocytosis and long-term depression in behavioural sensitization: relevance to treatment of brain disorders, including drug addiction | journal = British Journal of Pharmacology | volume = 153 Suppl 1 | issue = S1 | pages = S389-95 | date = March 2008 | pmid = 18059315 | pmc = 2268058 | doi = 10.1038/sj.bjp.0707616 }}</ref>