Editing AMPA receptor (section)

====Molecular and signaling response to LTP-inducing stimuli====
The mechanism for LTP has long been a topic of debate, but, recently, mechanisms have come to some consensus. AMPARs play a key role in this process, as one of the key indicators of LTP induction is the increase in the ratio of AMPAR to NMDARs following high-frequency stimulation. The idea is that AMPARs are trafficked from the dendrite into the synapse and incorporated through some series of signaling cascades.

AMPARs are initially regulated at the transcriptional level at their 5' promoter regions. There is significant evidence pointing towards the transcriptional control of AMPA receptors in longer-term memory through cAMP response element-binding protein ([[CREB]]) and [[Mitogen-activated protein kinases]] (MAPK).<ref>{{cite journal | vauthors = Perkinton MS, Sihra TS, Williams RJ | title = Ca(2+)-permeable AMPA receptors induce phosphorylation of cAMP response element-binding protein through a phosphatidylinositol 3-kinase-dependent stimulation of the mitogen-activated protein kinase signaling cascade in neurons | journal = The Journal of Neuroscience | volume = 19 | issue = 14 | pages = 5861–74 | date = July 1999 | pmid = 10407026 | pmc = 6783096 | doi = 10.1523/JNEUROSCI.19-14-05861.1999 }}</ref> Messages are translated on the rough [[endoplasmic reticulum]] (rough ER) and modified there. Subunit compositions are determined at the time of modification at the rough ER.<ref name="Greger et al. 2002"/> After post-ER processing in the Golgi apparatus, AMPARs are released into the perisynaptic membrane as a reserve waiting for the LTP process to be initiated.

The first key step in the process following glutamate binding to NMDARs is the influx of calcium through the NMDA receptors and the resultant activation of [[Ca2+/calmodulin-dependent protein kinase II|Ca<sup>2+</sup>/calmodulin-dependent protein kinase]] (CaMKII).<ref name="pmid8385124">{{cite journal | vauthors = Fukunaga K, Stoppini L, Miyamoto E, Muller D | title = Long-term potentiation is associated with an increased activity of Ca2+/calmodulin-dependent protein kinase II | journal = The Journal of Biological Chemistry | volume = 268 | issue = 11 | pages = 7863–7 | date = April 1993 | doi = 10.1016/S0021-9258(18)53037-4 | pmid = 8385124 | doi-access = free }}</ref> Blocking either this influx or the activation of CaMKII prevents LTP, showing that these are necessary mechanisms for LTP.<ref name="pmid11994750">{{cite journal | vauthors = Lisman J, Schulman H, Cline H | title = The molecular basis of CaMKII function in synaptic and behavioural memory | journal = Nature Reviews. Neuroscience | volume = 3 | issue = 3 | pages = 175–90 | date = March 2002 | pmid = 11994750 | doi = 10.1038/nrn753 | s2cid = 5844720 }}</ref> In addition, profusion of CaMKII into a synapse causes LTP, showing that it is a causal and sufficient mechanism.<ref name="pmid9405465">{{cite journal | vauthors = Mammen AL, Kameyama K, Roche KW, Huganir RL | title = Phosphorylation of the alpha-amino-3-hydroxy-5-methylisoxazole4-propionic acid receptor GluR1 subunit by calcium/calmodulin-dependent kinase II | journal = The Journal of Biological Chemistry | volume = 272 | issue = 51 | pages = 32528–33 | date = December 1997 | pmid = 9405465 | doi = 10.1074/jbc.272.51.32528 | doi-access = free }}</ref>

CaMKII has multiple modes of activation to cause the incorporation of AMPA receptors into the perisynaptic membrane. CAMKII enzyme is eventually responsible for the development of the actin cytoskeleton of neuronal cells and, eventually, for the dendrite and axon development (synaptic plasticity).<ref>{{cite journal | vauthors = Ebert DH, Greenberg ME | title = Activity-dependent neuronal signalling and autism spectrum disorder | journal = Nature | volume = 493 | issue = 7432 | pages = 327–37 | date = January 2013 | pmid = 23325215 | pmc = 3576027 | doi = 10.1038/nature11860 | bibcode = 2013Natur.493..327E }}</ref> The first is direct phosphorylation of synaptic-associated protein 97([[SAP97]]), a [[Scaffold protein|scaffolding protein]].<ref name="pmid15044483">{{cite journal | vauthors = Mauceri D, Cattabeni F, Di Luca M, Gardoni F | title = Calcium/calmodulin-dependent protein kinase II phosphorylation drives synapse-associated protein 97 into spines | journal = The Journal of Biological Chemistry | volume = 279 | issue = 22 | pages = 23813–21 | date = May 2004 | pmid = 15044483 | doi = 10.1074/jbc.M402796200 | doi-access = free }}</ref> First, SAP-97 and Myosin-VI, a motor protein, are bound as a complex to the C-terminus of AMPARs. Following phosphorylation by CaMKII, the complex moves into the perisynaptic membrane.<ref name="pmid12050163">{{cite journal | vauthors = Wu H, Nash JE, Zamorano P, Garner CC | title = Interaction of SAP97 with minus-end-directed actin motor myosin VI. Implications for AMPA receptor trafficking | journal = The Journal of Biological Chemistry | volume = 277 | issue = 34 | pages = 30928–34 | date = August 2002 | pmid = 12050163 | doi = 10.1074/jbc.M203735200 | doi-access = free }}</ref> The second mode of activation is through the MAPK pathway. CaMKII activates the Ras proteins, which go on to activate p42/44 MAPK, which drives AMPAR insertion directly into the perisynaptic membrane.<ref name="pmid12202034">{{cite journal | vauthors = Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R | title = Ras and Rap control AMPA receptor trafficking during synaptic plasticity | journal = Cell | volume = 110 | issue = 4 | pages = 443–55 | date = August 2002 | pmid = 12202034 | doi = 10.1016/S0092-8674(02)00897-8 | s2cid = 12858091 | doi-access = free }}</ref>