Proteins Involved in the Trafficking and Functional Synaptic Expression of AMPA and KA Receptors

α-Amino-3-hydroxy-5-methylisoxazolepropionate receptors (AMPARs) mediate the majority of fast synaptic transmission in the mammalian central nervous system, play a central role in synapse stabilisation and plasticity, and their prolonged activation is potently neurotoxic. The functional roles of kainate receptors (KARs) are less well defined but they play a role in some forms of synaptic plasticity. Both receptor types have been shown to be highly developmentally and activity-dependently regulated and their functional synaptic expression is under tight cellular regulation. The molecular and cellular mechanisms that regulate the synaptic localisation and functional expression of AMPARs and KARs are objects of concerted research. There has been significant progress towards elucidating some of the processes involved with the discovery of an array of proteins that selectively interact with individual AMPAR and KAR subunits. These proteins have been implicated in, among other things, the regulation of post-translational modification, targeting and trafficking, surface expression, and anchoring. The aim of this review is to present an overview of the major interacting proteins and suggest how they may fit into the hierarchical series of events controlling the trafficking of AMPARs and KARs

Removal of AMPA receptors (AMPARs) from synapses is preceded by transient endocytosis of extrasynaptic AMPARs

AMPA receptors (AMPARs) are dynamically regulated at synapses, but the time course and location of their exocytosis and endocytosis are not known. Therefore, we have used ecliptic pHluorin-tagged glutamate receptor 2 to visualize changes in AMPAR surface expression in real time. We show that synaptic and extrasynaptic AMPARs respond very differently to NMDA receptor activation; there is a rapid internalization of extrasynaptic AMPARs that precedes the delayed removal of synaptic AMPARs

Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma

Abstract: The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy

A comparative analysis of whole genome sequencing of esophageal adenocarcinoma pre- and post-chemotherapy

The scientific community has avoided using tissue samples from patients that have been exposed to systemic chemotherapy to infer the genomic landscape of a given cancer. Esophageal adenocarcinoma is a heterogeneous, chemoresistant tumor for which the availability and size of pretreatment endoscopic samples are limiting. This study compares whole-genome sequencing data obtained from chemo-naive and chemo-treated samples. The quality of whole-genomic sequencing data is comparable across all samples regardless of chemotherapy status. Inclusion of samples collected post-chemotherapy increased the proportion of late-stage tumors. When comparing matched pre- and post-chemotherapy samples from 10 cases, the mutational signatures, copy number, and SNV mutational profiles reflect the expected heterogeneity in this disease. Analysis of SNVs in relation to allele-specific copy-number changes pinpoints the common ancestor to a point prior to chemotherapy. For cases in which pre- and post-chemotherapy samples do show substantial differences, the timing of the divergence is near-synchronous with endoreduplication. Comparison across a large prospective cohort (62 treatment-naive, 58 chemotherapy-treated samples) reveals no significant differences in the overall mutation rate, mutation signatures, specific recurrent point mutations, or copy-number events in respect to chemotherapy status. In conclusion, whole-genome sequencing of samples obtained following neoadjuvant chemotherapy is representative of the genomic landscape of esophageal adenocarcinoma. Excluding these samples reduces the material available for cataloging and introduces a bias toward the earlier stages of cancer.This study was partly funded by a project grant from Cancer Research UK. R.C.F. is funded by an NIHR Professorship and receives core funding from the Medical Research Council and infrastructure support from the Biomedical Research Centre and the Experimental Cancer Medicine Centre. We acknowledge the support of The University of Cambridge, Cancer Research UK (C14303/A17197) and Hutchison Whampoa Limited