GRIP1 interlinks N-cadherin and AMPA receptors at vesicles to promote combined cargo transport into dendrites

Abstract

Significance Synapses form and change in response to neuronal activity, and they dynamically exchange transmembrane proteins over time. Most synaptic proteins are synthesized in the cell body and undergo long-distance vesicular transport powered by molecular motors along microtubules. Here we show that two synaptic key proteins (GluA2 and N-cadherin) are simultaneously delivered within distinct transport vesicles through motor proteins. Our data suggest that multidomain cargo adaptors tether synaptic proteins destined for the same subcellular compartment. We propose that vesicular presorting is an alternative mechanism to efficiently supply synapses.

Calpains and neuronal damage in the ischemic brain: The swiss knife in synaptic injury

“…Similarly, incubation of synaptic membranes with purified calpain 1 in presence of Ca 2+ induced the cleavage of the GRIP, with the production of several fragments with apparent molecular mass of 74, 55, 49 and 45 kDa (Wyszynski et al, 1999), in accordance with the results obtained in brain sections incubated in presence of Ca 2+ . The molecular weight of the calpain-generated GRIP products indicates that some of the calpain cleavage sites are located within PDZ domains 4 and 5, which are known to be the binding sites for GluA2 (Heisler et al, 2014). These results suggest that calpain truncation might disrupt the interaction between GRIP and GluA2.…”

“…GRIP1 was recently shown to act as a scaffold protein involved in the combined delivery of AMPAR and N-cadherin into dendrites. Accordingly, interference with GluA2-GRIP1 binding reduced GluA2 and N-cadherin at the cell surface, significantly decreased the number of dendritic protrusions and induced a loss of synaptic contacts (Heisler et al, 2014). Excitotoxic stimulation of cultured organotypic hippocampal slices with NMDA induced a modest but significant decrease in the 130 kDa full length GRIP and the generation of 55, 49 and 45 kDa cleavage products, by a mechanism sensitive to calpain inhibitors .…”

The kinesin KIF21B participates in the cell surface delivery of γ2 subunit-containing GABAA receptors

“…For instance N-Cadherin connects to both KIF3 (Teng et al, 2005) and KIF5 (Heisler et al, 2014). Whether alternative motors mediate alternative processes is currently barely understood.…”

The classic cadherins in synaptic specificity

“…By definition, all classic cadherins bind the catenins and catenins are critical for synapse formation, but some cadherins have been shown to interact directly and indirectly with other synaptic proteins including glutamate receptors (AMPA, NMDA, and kainate type), scaffolding proteins (AKAP79/150, GRIP), and signaling molecules (Vangl2, p38 MAPK). 95,[107][108][109][110][111] Nonetheless, the precise signaling mechanisms used by cadherins during the process of synaptic specificity remain unknown. Another unresolved question is at what stage in synapse development are cadherins required?…”