Rapid glutamate receptor 2 trafficking during retinal degeneration

Abstract

BackgroundRetinal degenerations, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), are characterized by photoreceptor loss and anomalous remodeling of the surviving retina that corrupts visual processing and poses a barrier to late-stage therapeutic interventions in particular. However, the molecular events associated with retinal remodeling remain largely unknown. Given our prior evidence of ionotropic glutamate receptor (iGluR) reprogramming in retinal degenerations, we hypothesized that the edited glutamate receptor 2 (GluR2) subunit and its trafficking may be modulated in retinal degenerations.ResultsAdult albino Balb/C mice were exposed to intense light for 24 h to induce light-induced retinal degeneration (LIRD). We found that prior to the onset of photoreceptor loss, protein levels of GluR2 and related trafficking proteins, including glutamate receptor-interacting protein 1 (GRIP1) and postsynaptic density protein 95 (PSD-95), were rapidly increased. LIRD triggered neuritogenesis in photoreceptor survival regions, where GluR2 and its trafficking proteins were expressed in the anomalous dendrites. Immunoprecipitation analysis showed interaction between KIF3A and GRIP1 as well as PSD-95, suggesting that KIF3A may mediate transport of GluR2 and its trafficking proteins to the novel dendrites. However, in areas of photoreceptor loss, GluR2 along with its trafficking proteins nearly vanished in retracted retinal neurites.ConclusionsAll together, LIRD rapidly triggers GluR2 plasticity, which is a potential mechanism behind functionally phenotypic revisions of retinal neurons and neuritogenesis during retinal degenerations.

Selective synaptic targeting of the excitatory and inhibitory presynaptic organizers, FGF22 and FGF7

“…2C,D). What is common regarding the function of SAP102, PSD95, KIF3A and KIF17 is that they are all involved in the development of excitatory synapses; SAP102 and PSD95 are scaffolding proteins at excitatory synapses and are crucial for their differentiation (Ehrlich et al, 2007;Elias et al, 2008;Elias and Nicoll, 2007;Murata and Constantine-Paton, 2013;Zheng et al, 2011), and KIF3A and KIF17 are involved in AMPA and NMDA receptor transportation (Jo et al, 1999;Lin et al, 2012;Setou et al, 2000). We also found that SAP102 is an adaptor for the targeting of FGF22 to excitatory synapses (Fig.…”

“…For the excitatory presynaptic organizer FGF22, we found that motor proteins KIF3A and KIF17 and a scaffolding protein at excitatory synapses, SAP102, contribute to the targeting of the protein to excitatory synapses. Accumulating data suggest that KIF3A, KIF17 and SAP102 are involved in the early stage of excitatory synapse formation: (1) KIF3A appears to transport the GluR2 subunit to newly formed dendritic processes after lightinduced retinal degeneration (Lin et al, 2012); (2) KIF17 transports NMDA receptors containing the GluN2B subunit (Setou et al, 2000), which is the dominant GluN2 subunit in the early stage of synaptic development (Bellone and Nicoll, 2007); and (3) SAP102 is expressed earlier than PSD95 (Elias et al, 2008;Sans et al, 2000) and has a role in trafficking and anchoring of the GluN2B subunit to immature synapses (Washbourne et al, 2004). As synaptogenesis proceeds, SAP102-dependent functions are shifted to PSD95-dependent functions, including an increase in the number of synaptic AMPA receptors and a switch of the NMDA receptor subunit from GluN2B to GluN2A (Elias et al, 2008;Sanz-Clemente et al, 2013).…”

“…We focused on four KIFs -KIF5, KIF3A, KIF17 and KIF21B, because these KIFs act as molecular motors for the intracellular transport of postsynaptic neurotransmitter receptors and/or are enriched in dendrites. KIF5 is involved in the transportation of the GABA A receptor, glycine receptor and AMPA receptor (Maas et al, 2006;Nakajima et al, 2012;Setou et al, 2002;Smith et al, 2006); KIF3A localizes to excitatory postsynaptic terminals and is involved in AMPA receptor transportation (Lin et al, 2012); KIF17 is a dendritic motor involved in NMDA receptor transportation (Jo et al, 1999;Setou et al, 2000); and KIF21B is highly enriched in dendrites (Marszalek et al, 1999). To examine whether these KIFs are involved in FGF22 transport, we generated GFP-tagged dominant negative (DN) mutants for KIF5, KIF3A and KIF17, and short hairpin RNA (shRNA) for KIF21B (Labonté et al, 2013).…”

Cell Surface Translocation of Annexin A2 Facilitates Glutamate-induced Extracellular Proteolysis

“…Despite intensive research, the mechanisms that contribute to glutamate-induced cellular loss are yet to be elucidated. In neurodegenerative diseases like age-related macular degeneration and retinitis pigmentosa, glutamate excitotoxicity has been linked to successive loss of photoreceptor cells (5). To have a better understanding of the mechanistic events of glutamate excitotoxicity that lead to retinal degeneration, we investigated the glutamate-induced, Ca 2ϩ -mediated signaling events in a cone-photoreceptor cell line, 661W.…”

Thyroid-specific inactivation of KIF3A alters the TSH signaling pathway and leads to hypothyroidism

“…The kinesin 2 molecular motor is known to participate to "non intraflagellar" transport in the cell, like retrograde traffic between the Golgi and the endoplasmic reticulum (ER) (Stauber et al 2006), endosome and lysosome transports (Bananis et al 2004;Brown et al 2005), endocytosis and recycling of cell surface receptors like transferrin, cubulin and megalin receptors, or of other proteins like Clc-5, the H + /Cl − exchange transporter (Schonteich et al 2008;Reed et al 2010). The KIF3 molecular motor also plays an important role in the transport of vesicles containing GluR2 and GLUT4 receptors or MT1-MMP and MMP-9 metalloproteinases from the cytosol to the plasma membrane (Imamura et al 2003;Wiesner et al 2010;Hanania et al 2012;Lin et al 2012). Unfortunately, we were unable to analyze the intracellular traffic or the cell surface expression of the TSH receptor in vivo or in vitro, due to the lack of specific antibody working on tissue sections (and probably also to the very low expression of the TSH receptor at the thyrocyte surface) and the unexpected consequence of Kif3a inactivation on TSH receptor expression directed by lentivirus infection.…”