{"id":7,"date":"2019-11-28T15:04:16","date_gmt":"2019-11-28T15:04:16","guid":{"rendered":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/?page_id=2"},"modified":"2022-03-08T11:16:15","modified_gmt":"2022-03-08T11:16:15","slug":"projects","status":"publish","type":"page","link":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/projects\/","title":{"rendered":"Current projects"},"content":{"rendered":"\n<h2 class=\"wp-block-heading\" id=\"structure-and-biophysics-of-major-ampa-receptor-complexes\">Structure and biophysics of major AMPA receptor complexes<\/h2>\n\n\n\n<p>AMPAR activation by glutamate involves a spectrum of conformational transitions referred to as \u2018gating\u2019. These ultimately open the channel\u2019s gate to permit cation flux and membrane depolarisation. Using a combination of electron cryomicroscopy (cryo-EM), patch-clamp electrophysiology, molecular dynamics simulations, and mass-spectrometry, we study:<\/p>\n\n\n\n<ol class=\"wp-block-list\" type=\"1\"><li>the organisation and stoichiometry of predominant AMPAR-auxiliary subunit complexes<\/li><li>how auxiliary subunits influence transitions in the AMPAR gating cycle<\/li><li>the identity, binding sites and role of AMPAR-associated annular lipids<\/li><li>the development of therapeutic ligands targeting predominant AMPAR complexes (in collaboration with AstraZeneca and LifeArc).<\/li><\/ol>\n\n\n\n<div class=\"wp-block-genesis-blocks-gb-columns gb-layout-columns-2 gb-2-col-equal\"><div class=\"gb-layout-column-wrap gb-block-layout-column-gap-2 gb-is-responsive-column\">\n<div class=\"wp-block-genesis-blocks-gb-column gb-block-layout-column\"><div class=\"gb-block-layout-column-inner\">\n<figure class=\"wp-block-video\"><video height=\"782\" style=\"aspect-ratio: 1138 \/ 782;\" width=\"1138\" autoplay controls loop src=\"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-content\/uploads\/sites\/32\/movie_full-length.mp4\"><\/video><figcaption>cryo-EM structure of an octameric AMPAR complex: GluA1 (blue), GluA2 (red), Tarp gamma8 (green), CNIH2 (yellow)<\/figcaption><\/figure>\n<\/div><\/div>\n\n\n\n<div class=\"wp-block-genesis-blocks-gb-column gb-block-layout-column\"><div class=\"gb-block-layout-column-inner\">\n<div class=\"wp-block-image\"><figure class=\"aligncenter size-full\"><a href=\"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-content\/uploads\/sites\/32\/trace-e1646738127428.png\"><img loading=\"lazy\" decoding=\"async\" width=\"346\" height=\"358\" src=\"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-content\/uploads\/sites\/32\/trace-e1646738127428.png\" alt=\"\" class=\"wp-image-166\"\/><\/a><figcaption>Response of GluA1 or GluA1+TARP gamma8 to a brief pulse of glutamate<\/figcaption><\/figure><\/div>\n<\/div><\/div>\n<\/div><\/div>\n\n\n\n<h2 class=\"wp-block-heading\" id=\"regulation-of-ampa-receptor-organisation-at-potentiated-synapses\">Regulation of AMPA receptor organisation at potentiated synapses<\/h2>\n\n\n\n<p>A hallmark of learning (i.e. the encoding and storage of information) is the growth and potentiation of synapses. This process requires the recruitment of AMPARs into the post-synaptic density (PSD) and their accumulation into receptor nano-clusters. A central question is the nature of the machinery facilitating AMPAR organisation at potentiated synapses. To address this we:<\/p>\n\n\n\n<ol class=\"wp-block-list\" type=\"1\"><li>investigate essential AMPAR clustering components, through recordings of neurons expressing modified AMPAR complexes (expressed virally in genetically modified mice)&nbsp;<\/li><li>image the sub-synaptic distribution of AMPAR varieties using 3D STORM and STED, prior to and after synapse potentiation (induced electrically or via 2-photon glutamate uncaging)<\/li><li>identify AMPAR synaptic clustering\/anchoring proteins using proximity labelling approaches<\/li><li>re-constitute core clustering elements (identified through the above approaches) together with AMPARs in synthetic \u2018hemi-synapses\u2019<\/li><\/ol>\n\n\n\n<div class=\"wp-block-genesis-blocks-gb-columns gb-layout-columns-2 gb-2-col-equal\"><div class=\"gb-layout-column-wrap gb-block-layout-column-gap-2 gb-is-responsive-column\">\n<div class=\"wp-block-genesis-blocks-gb-column gb-block-layout-column\"><div class=\"gb-block-layout-column-inner\">\n<div class=\"wp-block-image\"><figure class=\"aligncenter size-full\"><a href=\"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-content\/uploads\/sites\/32\/Project-2a.jpg\"><img loading=\"lazy\" decoding=\"async\" width=\"968\" height=\"572\" src=\"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-content\/uploads\/sites\/32\/Project-2a.jpg\" alt=\"\" class=\"wp-image-130\" srcset=\"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-content\/uploads\/sites\/32\/Project-2a.jpg 968w, https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-content\/uploads\/sites\/32\/Project-2a-300x177.jpg 300w, https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-content\/uploads\/sites\/32\/Project-2a-768x454.jpg 768w\" sizes=\"auto, (max-width: 968px) 100vw, 968px\" \/><\/a><figcaption>Alignment of pre-synapse (pink stain, Basoon) and post-synapse (PSD-95, green). Confocal (left) versus 3D STORM (right). Scale bar = 100 nm.<\/figcaption><\/figure><\/div>\n<\/div><\/div>\n\n\n\n<div class=\"wp-block-genesis-blocks-gb-column gb-block-layout-column\"><div class=\"gb-block-layout-column-inner\">\n<div class=\"wp-block-image\"><figure class=\"aligncenter size-full\"><a href=\"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-content\/uploads\/sites\/32\/Project-2b.png\"><img loading=\"lazy\" decoding=\"async\" width=\"968\" height=\"572\" src=\"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-content\/uploads\/sites\/32\/Project-2b.png\" alt=\"\" class=\"wp-image-131\" srcset=\"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-content\/uploads\/sites\/32\/Project-2b.png 968w, https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-content\/uploads\/sites\/32\/Project-2b-300x177.png 300w, https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-content\/uploads\/sites\/32\/Project-2b-768x454.png 768w\" sizes=\"auto, (max-width: 968px) 100vw, 968px\" \/><\/a><figcaption>Simulated synaptic AMPAR responses<\/figcaption><\/figure><\/div>\n<\/div><\/div>\n<\/div><\/div>\n\n\n\n<p><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Structure and biophysics of major AMPA receptor complexes AMPAR activation by glutamate involves a spectrum of conformational transitions referred to as \u2018gating\u2019. These ultimately open the channel\u2019s gate to permit cation flux and membrane depolarisation. Using a combination of electron cryomicroscopy (cryo-EM), patch-clamp electrophysiology, molecular dynamics simulations, and mass-spectrometry, we study: the organisation and stoichiometry [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"open","template":"","meta":{"_genesis_hide_title":false,"_genesis_hide_breadcrumbs":false,"_genesis_hide_singular_image":false,"_genesis_hide_footer_widgets":false,"_genesis_custom_body_class":"","_genesis_custom_post_class":"","_genesis_layout":"","footnotes":""},"categories":[],"class_list":{"0":"post-7","1":"page","2":"type-page","3":"status-publish","5":"entry"},"featured_image_src":null,"featured_image_src_square":null,"_links":{"self":[{"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-json\/wp\/v2\/pages\/7","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-json\/wp\/v2\/comments?post=7"}],"version-history":[{"count":18,"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-json\/wp\/v2\/pages\/7\/revisions"}],"predecessor-version":[{"id":186,"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-json\/wp\/v2\/pages\/7\/revisions\/186"}],"wp:attachment":[{"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-json\/wp\/v2\/media?parent=7"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www2.mrc-lmb.cam.ac.uk\/groups\/greger\/wp-json\/wp\/v2\/categories?post=7"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}