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Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions

To be highly reliable, synaptic transmission needs postsynaptic receptors (Rs) in precise apposition to the presynaptic release sites. At inhibitory synapses, the postsynaptic protein gephyrin self-assembles to form a scaffold that anchors glycine and GABA(A)Rs to the cytoskeleton, thus ensuring the...

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Autores principales: Pizzarelli, Rocco, Griguoli, Marilena, Zacchi, Paola, Petrini, Enrica Maria, Barberis, Andrea, Cattaneo, Antonino, Cherubini, Enrico
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351109/
https://www.ncbi.nlm.nih.gov/pubmed/31356900
http://dx.doi.org/10.1016/j.neuroscience.2019.07.036
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author Pizzarelli, Rocco
Griguoli, Marilena
Zacchi, Paola
Petrini, Enrica Maria
Barberis, Andrea
Cattaneo, Antonino
Cherubini, Enrico
author_facet Pizzarelli, Rocco
Griguoli, Marilena
Zacchi, Paola
Petrini, Enrica Maria
Barberis, Andrea
Cattaneo, Antonino
Cherubini, Enrico
author_sort Pizzarelli, Rocco
collection PubMed
description To be highly reliable, synaptic transmission needs postsynaptic receptors (Rs) in precise apposition to the presynaptic release sites. At inhibitory synapses, the postsynaptic protein gephyrin self-assembles to form a scaffold that anchors glycine and GABA(A)Rs to the cytoskeleton, thus ensuring the accurate accumulation of postsynaptic receptors at the right place. This protein undergoes several post-translational modifications which control protein–protein interaction and downstream signaling pathways. In addition, through the constant exchange of scaffolding elements and receptors in and out of synapses, gephyrin dynamically regulates synaptic strength and plasticity. The aim of the present review is to highlight recent findings on the functional role of gephyrin at GABAergic inhibitory synapses. We will discuss different approaches used to interfere with gephyrin in order to unveil its function. In addition, we will focus on the impact of gephyrin structure and distribution at the nanoscale level on the functional properties of inhibitory synapses as well as the implications of this scaffold protein in synaptic plasticity processes. Finally, we will emphasize how gephyrin genetic mutations or alterations in protein expression levels are implicated in several neuropathological disorders, including autism spectrum disorders, schizophrenia, temporal lobe epilepsy and Alzheimer's disease, all associated with severe deficits of GABAergic signaling. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
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spelling pubmed-73511092020-07-15 Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions Pizzarelli, Rocco Griguoli, Marilena Zacchi, Paola Petrini, Enrica Maria Barberis, Andrea Cattaneo, Antonino Cherubini, Enrico Neuroscience Article To be highly reliable, synaptic transmission needs postsynaptic receptors (Rs) in precise apposition to the presynaptic release sites. At inhibitory synapses, the postsynaptic protein gephyrin self-assembles to form a scaffold that anchors glycine and GABA(A)Rs to the cytoskeleton, thus ensuring the accurate accumulation of postsynaptic receptors at the right place. This protein undergoes several post-translational modifications which control protein–protein interaction and downstream signaling pathways. In addition, through the constant exchange of scaffolding elements and receptors in and out of synapses, gephyrin dynamically regulates synaptic strength and plasticity. The aim of the present review is to highlight recent findings on the functional role of gephyrin at GABAergic inhibitory synapses. We will discuss different approaches used to interfere with gephyrin in order to unveil its function. In addition, we will focus on the impact of gephyrin structure and distribution at the nanoscale level on the functional properties of inhibitory synapses as well as the implications of this scaffold protein in synaptic plasticity processes. Finally, we will emphasize how gephyrin genetic mutations or alterations in protein expression levels are implicated in several neuropathological disorders, including autism spectrum disorders, schizophrenia, temporal lobe epilepsy and Alzheimer's disease, all associated with severe deficits of GABAergic signaling. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries. Elsevier Science 2020-07-15 /pmc/articles/PMC7351109/ /pubmed/31356900 http://dx.doi.org/10.1016/j.neuroscience.2019.07.036 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Pizzarelli, Rocco
Griguoli, Marilena
Zacchi, Paola
Petrini, Enrica Maria
Barberis, Andrea
Cattaneo, Antonino
Cherubini, Enrico
Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions
title Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions
title_full Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions
title_fullStr Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions
title_full_unstemmed Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions
title_short Tuning GABAergic Inhibition: Gephyrin Molecular Organization and Functions
title_sort tuning gabaergic inhibition: gephyrin molecular organization and functions
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351109/
https://www.ncbi.nlm.nih.gov/pubmed/31356900
http://dx.doi.org/10.1016/j.neuroscience.2019.07.036
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