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      Noncanonical Metabotropic Glutamate Receptor 5 Signaling in Alzheimer's Disease

      Author(s): 1 , 2 , 1
      Publication date Created:
      Publication date (Print):
      Journal: Annual Review of Pharmacology and Toxicology
      Publisher: Annual Reviews

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          Abstract

          Metabotropic glutamate receptor 5 (mGluR5) is ubiquitously expressed in brain regions responsible for memory and learning. It plays a key role in modulating rapid changes in synaptic transmission and plasticity. mGluR5 supports long-term changes in synaptic strength by regulating the transcription and translation of essential synaptic proteins. β-Amyloid 42 (Aβ42) oligomers interact with a mGluR5/cellular prion protein (PrP C) complex to disrupt physiological mGluR5 signal transduction. Aberrant mGluR5 signaling and associated synaptic failure are considered an emerging pathophysiological mechanism of Alzheimer's disease (AD). Therefore, mGluR5 represents an attractive therapeutic target for AD, and recent studies continue to validate the efficacy of various mGluR5 allosteric modulators in improving memory deficits and mitigating disease pathology. However, sex-specific differences in the pharmacology of mGluR5 and activation of noncanonical signaling downstream of the receptor suggest that its utility as a therapeutic target in female AD patients needs to be reconsidered.

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          AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.

          Joungmok Kim, Mondira Kundu, Benoit Viollet … (2011)
          Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.
          Article 0 comments Cited 1296 times – based on 0 reviews     Review now
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            Metabotropic glutamate receptors: physiology, pharmacology, and disease.

            Colleen M. Niswender, P. Conn (2010)
            The metabotropic glutamate receptors (mGluRs) are family C G-protein-coupled receptors that participate in the modulation of synaptic transmission and neuronal excitability throughout the central nervous system. The mGluRs bind glutamate within a large extracellular domain and transmit signals through the receptor protein to intracellular signaling partners. A great deal of progress has been made in determining the mechanisms by which mGluRs are activated, proteins with which they interact, and orthosteric and allosteric ligands that can modulate receptor activity. The widespread expression of mGluRs makes these receptors particularly attractive drug targets, and recent studies continue to validate the therapeutic utility of mGluR ligands in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, anxiety, depression, and schizophrenia.
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              APP processing and synaptic function.

              Flavio Kamenetz, Taisuke Tomita, Helen V. Hsieh … (2003)
              A large body of evidence has implicated Abeta peptides and other derivatives of the amyloid precursor protein (APP) as central to the pathogenesis of Alzheimer's disease (AD). However, the functional relationship of APP and its proteolytic derivatives to neuronal electrophysiology is not known. Here, we show that neuronal activity modulates the formation and secretion of Abeta peptides in hippocampal slice neurons that overexpress APP. In turn, Abeta selectively depresses excitatory synaptic transmission onto neurons that overexpress APP, as well as nearby neurons that do not. This depression depends on NMDA-R activity and can be reversed by blockade of neuronal activity. Synaptic depression from excessive Abeta could contribute to cognitive decline during early AD. In addition, we propose that activity-dependent modulation of endogenous Abeta production may normally participate in a negative feedback that could keep neuronal hyperactivity in check. Disruption of this feedback system could contribute to disease progression in AD.
              Article 0 comments Cited 434 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Title: Annual Review of Pharmacology and Toxicology
                Abbreviated Title: Annu. Rev. Pharmacol. Toxicol.
                Publisher: Annual Reviews
                ISSN (Print): 0362-1642
                ISSN (Electronic): 1545-4304
                Publication date Created: January 06 2022
                Publication date (Print): January 06 2022
                Volume: 62
                Issue: 1
                Pages: 235-254
                Affiliations
                [1 ]University of Ottawa Brain and Mind Research Institute and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;,
                [2 ]Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
                Article
                DOI: 10.1146/annurev-pharmtox-021821-091747
                PubMed ID: 34516293
                SO-VID: 2447d9e1-5242-4982-a123-31f84e9fc4fc
                Copyright © © 2022
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