Le neurotransmetteur de la grande majorit\u00e9 des synapses excitatrices, le glutamate, exerce aussi des r\u00f4les modulateurs via l’activation de r\u00e9cepteurs coupl\u00e9s aux prot\u00e9ines G, aussi appel\u00e9s les r\u00e9cepteurs m\u00e9tabotropiques du glutamate (mGluR). Ces r\u00e9cepteurs sont des dim\u00e8res constitutifs. Huit g\u00e8nes codent pour les sous-unit\u00e9s des mGluR, et nous avons r\u00e9cemment montr\u00e9 que ces huit sous-unit\u00e9s peuvent former des h\u00e9t\u00e9rodim\u00e8res de composition d\u00e9finie, augmentant ainsi le nombre possible de r\u00e9cepteurs de huit (homodim\u00e8res) \u00e0 24 (en incluant les h\u00e9t\u00e9rodim\u00e8res possibles). Parmi ces r\u00e9cepteurs, ceux contenant la sous-unit\u00e9 mGlu2 constituent des cibles int\u00e9ressantes pour le traitement de l’anxi\u00e9t\u00e9 ou de la schizophr\u00e9nie. Ainsi, de nombreuses entreprises pharmaceutiques ont d\u00e9velopp\u00e9 des agonistes et des modulateurs allost\u00e9riques positifs de mGlu2. Cependant, ces compos\u00e9s ont \u00e9chou\u00e9 dans les essais cliniques de phase 3 en raison d’effets secondaires ou de manque d\u2019efficacit\u00e9, qui pourraient \u00eatre dus aux actions “off-target” de ces compos\u00e9s ou \u00e0 l’existence de mGlu h\u00e9t\u00e9rodim\u00e9riques. Dans cette \u00e9tude impliquant 5 \u00e9quipes fran\u00e7aises, dont deux de l’IGF (Pin\/Rondard et Valjent) nous d\u00e9crivons des nanobodies (des anticorps simple cha\u00eene de lamas) qui agissent sp\u00e9cifiquement sur les homodim\u00e8res mGlu2, comme des modulateurs allost\u00e9riques positifs (ils augmentent les effets d’un agoniste). Ces nanobodies sont donc les premiers compos\u00e9s s\u00e9lectifs des r\u00e9cepteurs mGlu2 homodim\u00e9riques. Nous montrons qu\u2019apr\u00e8s injection dans le cerveau, l’un d’eux inhibe la consolidation de la m\u00e9moire de peur, processus dans lequel le r\u00e9cepteur mGlu2 homodim\u00e9rique est impliqu\u00e9. Cette \u00e9tude montre le potentiel des nanobodies comme outils pharmacologiques mais aussi comme agents th\u00e9rapeutiques potentiels pour contr\u00f4ler l’activit\u00e9 des r\u00e9cepteurs dans le cerveau.<\/p>\n
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The transmitter of most excitatory synapses in the brain, glutamate, also has modulatory role through the activation of G protein-coupled receptors, the so-called metabotropic glutamate receptors (mGluRs). The mGlu receptors are mandatory dimers. Eight genes encode mGlu subunits, and we recently reported that they can assemble into heterodimers, increasing the number of possible mGlu receptors from 8 homodimers, to 24 different subtypes including the possible heterodimers. These receptors are considered as possible new targets for the treatment of various brain diseases. Among them, mGlu2 containing receptors are of interest for the treatment of anxiety and schizophrenia. As such most pharmaceutical companies developed mGlu2 receptor agonists and positive allosteric modulators, but all failed in clinical trials, mostly due to side effects or lack of efficacy. This may be partly due to the off- target effect of allosteric modulators, or the existence of mGlu2 heterodimers. In the present study, involving five research groups in France including two from the IGF (Pin\/Rondard and Valjent), we identified nanobodies (single chain antibodies from lamas) specifically acting at mGlu2 homodimers, with positive allosteric properties (they enhance the action of agonist). These nanobodies are then the first highly selective positive modulators of mGlu2 homodimers. We show that injected into the brain, these nanobodies inhibit the consolidation of fear memory, implicating hippocampal mGlu2 homodimers in this process. This study reveals the great potential of nanobodies as pharmacological tools and possibly as therapeutic agents for controlling brain receptors.<\/p>\n
R\u00e9f\u00e9rence:\u00a0Scholler P, Nevoltris D, de Bundel D, Bossi S, Moreno-Delgado D, Rovira X, M\u00f8ller TC, El Moustaine D, Mathieu M, Blanc E, McLean H, Dupuis E, Mathis G, Trinquet E, Daniel H, Valjent E, Baty D, Chames P, Rondard P, Pin JP. Allosteric\u00a0 nanobodies uncover a role of hippocampal mGlu2 receptor homodimers in contextual\u00a0 fear consolidation. Nat Commun. 2017 Dec 6;8(1):1967. doi: 10.1038\/s41467-017-01489-1.<\/p>\n
Link: http:\/\/rdcu.be\/AyD2<\/p>\n
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Contact chercheurs : <\/p>\n","protected":false},"excerpt":{"rendered":" Le neurotransmetteur de la grande majorit\u00e9 des synapses excitatrices, le glutamate, exerce aussi des r\u00f4les modulateurs via l’activation de r\u00e9cepteurs coupl\u00e9s aux prot\u00e9ines G, aussi appel\u00e9s les r\u00e9cepteurs m\u00e9tabotropiques du glutamate (mGluR). Ces r\u00e9cepteurs sont des dim\u00e8res constitutifs. Huit g\u00e8nes codent pour les sous-unit\u00e9s des mGluR, et nous avons r\u00e9cemment montr\u00e9 que ces huit sous-unit\u00e9s […]<\/p>\n","protected":false},"author":4,"featured_media":8667,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[25],"tags":[31],"class_list":["post-8664","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-uncategorized","tag-actualite-en"],"publishpress_future_action":{"enabled":false,"date":"2026-04-24 10:46:23","action":"change-status","newStatus":"draft","terms":[],"taxonomy":"category"},"publishpress_future_workflow_manual_trigger":{"enabledWorkflows":[]},"_links":{"self":[{"href":"https:\/\/www.neurosciences.asso.fr\/en\/wp-json\/wp\/v2\/posts\/8664","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.neurosciences.asso.fr\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.neurosciences.asso.fr\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.neurosciences.asso.fr\/en\/wp-json\/wp\/v2\/users\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/www.neurosciences.asso.fr\/en\/wp-json\/wp\/v2\/comments?post=8664"}],"version-history":[{"count":3,"href":"https:\/\/www.neurosciences.asso.fr\/en\/wp-json\/wp\/v2\/posts\/8664\/revisions"}],"predecessor-version":[{"id":8671,"href":"https:\/\/www.neurosciences.asso.fr\/en\/wp-json\/wp\/v2\/posts\/8664\/revisions\/8671"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.neurosciences.asso.fr\/en\/wp-json\/wp\/v2\/media\/8667"}],"wp:attachment":[{"href":"https:\/\/www.neurosciences.asso.fr\/en\/wp-json\/wp\/v2\/media?parent=8664"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.neurosciences.asso.fr\/en\/wp-json\/wp\/v2\/categories?post=8664"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.neurosciences.asso.fr\/en\/wp-json\/wp\/v2\/tags?post=8664"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
\nInstitut de G\u00e9nomique Fonctionnelle, CNRS, INSERM, Univ. Montpellier, F-34094, Montpellier, France.
\njean-philippe.pin@igf.cnrs.fr<\/a>
\nPhilippe.Rondard@igf.cnrs.fr<\/a><\/p>\n