To elucidate this relationship we developed a
To elucidate this relationship, we developed a spatial model of Ca-influx through N-methyl-D-aspartate receptor (NMDAR), CaMKII/PP1 activation, and AMPAR insertion in a realistic spine geometry. Using this model, we show that i) variables in membrane voltage mediated Ca-influx, particularly the number of active NMDAR and extracellular Ca levels, primarily regulate cytosolic protein dynamics through their impact on Ca dynamics. ii) AMPAR dynamics depend on a combination of membrane curvature effects, endoplasmic reticulum (ER) spatial distribution, cytosolic protein concentrations, and stargazin binding. iii) AMPAR levels depend on both exocytosis from cytosolic stores and, more significantly, 4-DAMP receptor of AMPAR from extrasynaptic membrane (ESM) regions on the dendrite.
Introduction Many properties of AMPARs are dictated by the edited GluA2 subunit (Geiger et al., 1995; Swanson et al., 1997). AMPARs without GluA2 are permeable to calcium and display an inwardly rectifying IV-relationship, as they are blocked by endogenous intracellular polyamines at positive potentials, (Bowie and Mayer, 1995; Kamboj et al., 1995; Koh et al., 1995). When compared with their GluA2-containing counterparts, CP-AMPARs display a greater channel conductance (Feldmeyer et al., 1999; Swanson et al., 1997) and faster kinetics (Geiger et al., 1995). Expression, assembly and trafficking of CP-AMPARs are essential to basal transmission at many central synapses, and play pivotal roles in several important forms of synaptic plasticity. At the same time, over activation of these receptors can be injurious, and is thought to be a major contributor to cell death following stroke and hypoxic–ischemic white matter damage in infants. In addition, the upregulation or dysfunction of CP-AMPARs appears to be a significant contributor in several neurological disease states including glioblastoma cell proliferation, chronic pain and drug addiction (Cull-Candy et al., 2006; Kwak and Weiss, 2006; Liu and Zukin, 2007). For these reasons there has been growing interest in the regulation and plasticity of CP-AMPARs. It has become clear that the diversity of native AMPAR properties is determined not only by AMPAR subunit composition and posttranslational modifications (such as phosphorylation; Lu and Roche, 2012), but also by the presence of auxiliary AMPAR subunits. Following the recognition that stargazin (γ-2) is a key regulator of AMPAR behaviour (Chen et al., 2000; Hashimoto et al., 1999), a number of related transmembrane AMPAR regulatory proteins have been identified (TARPs γ-3, -4, -5, -7, and -8) (Kato et al., 2007; Soto et al., 2009; Tomita et al., 2003). These various TARPs differ in their influence on AMPAR properties and display distinct, although partially overlapping, patterns of expression in the cerebellum (see Fig. 1) and elsewhere in the CNS (Fukaya et al., 2005; Tomita et al., 2003). Native AMPARs are thought to contain from one to four TARPs in addition to their core pore-forming subunits (Hastie et al., 2013; Kim et al., 2010; Shi et al., 2009); however, it is generally thought that only one type of TARP is present within a given AMPAR complex (Kato et al., 2007; Tomita et al., 2003). TARP association modifies several important aspects of AMPAR function. It increases their single-channel conductance (Soto et al., 2007, 2009; Tomita et al., 2005a), slows their deactivation and desensitization (Bedoukian et al., 2006; Cho et al., 2007; Korber et al., 2007; Milstein et al., 2007; Priel et al., 2005; Tomita et al., 2005a; Turetsky et al., 2005), attenuates voltage-dependent block by endogenous intracellular polyamines and modifies their pharmacological properties (Korber et al., 2007; Soto et al., 2007, 2009; Turetsky et al., 2005). TARPs also play a critical role in AMPAR trafficking, promoting AMPAR maturation (Vandenberghe et al., 2005), delivery to the cell surface and clustering at the synapse (Chen et al., 2000; Kato et al., 2007; Soto et al., 2009; Tomita et al., 2003; Vandenberghe et al., 2005). Recent evidence also suggests that TARPs are involved in the regulation of AMPAR number that occurs with long-term potentiation (LTP) or depression (LTD) of synaptic transmission in hippocampal pyramidal neurons (Tomita et al., 2005b) and in cerebellar Purkinje cells (Nomura et al., 2012). While the role of TARPs in the neuronal trafficking of GluA2-containing CI-AMPARs is relatively well characterized, their role in the regulation of CP-AMPAR expression is much less well understood.