Delineating the interactions between the cannabinoid CB2 receptor and its regulatory effectors; β-arrestins and G protein-coupled receptor kinases

Lade...
Vorschaubild
Dateien
Patel_2-85euuab87s7w2.pdf
Patel_2-85euuab87s7w2.pdfGröße: 1.39 MBDownloads: 20
Datum
2022
Autor:innen
Patel, Monica
Grimsey, Natasha L.
Javitch, Jonathan A.
Finlay, David B.
Glass, Michelle
Herausgeber:innen
Kontakt
ISSN der Zeitschrift
Electronic ISSN
ISBN
Bibliografische Daten
Verlag
Schriftenreihe
Auflagebezeichnung
DOI (zitierfähiger Link)
ArXiv-ID
Internationale Patentnummer
Angaben zur Forschungsförderung
Projekt
Open Access-Veröffentlichung
Open Access Green
Sammlungen
Core Facility der Universität Konstanz
Gesperrt bis
Titel in einer weiteren Sprache
Publikationstyp
Zeitschriftenartikel
Publikationsstatus
Published
Erschienen in
British Journal of Pharmacology (BJP). Wiley. 2022, 179(10), pp. 2223-2239. ISSN 0366-0826. eISSN 1476-5381. Available under: doi: 10.1111/bph.15748
Zusammenfassung

Background and Purpose
The cannabinoid CB2 receptor (CB2) is a promising therapeutic target for modulating inflammation. However, little is known surrounding the mechanisms underpinning CB2 desensitisation and regulation, particularly the role of G protein-coupled receptor kinases (GRKs). Here, we evaluated the role of six GRK isoforms in β-arrestin recruitment to CB2. Mutagenesis of several distal C-terminal aspartic acid residues was also performed in an attempt to delineate additional structural elements involved in the regulation of CB2.

Experimental Approach
In CB2-expressing HEK 293 cells, β-arrestin translocation was measured using real-time BRET assays. G protein dissociation BRET assays were performed to assess the activation and desensitisation of CB2 in the presence of β-arrestin 2.

Key Results
Overexpression of GRK isoforms 1-6 failed to considerably improve translocation of either β-arrestin 1 or β-arrestin 2 to CB2. Consistent with this, inhibition of endogenous GRK2/3 did not substantially reduce β-arrestin 2 translocation. Mutagenesis of C-terminal aspartic acid residues resulted in attenuation of β-arrestin 2 translocation, which translated to a reduction in desensitisation of G protein activation.

Conclusion and Implications
Our findings suggest that CB2 does not adhere to the classical GPCR regulatory paradigm, entailing GRK- and β-arrestin-mediated desensitisation. Instead, C-terminal aspartic acid residues may act as phospho-mimics to induce β-arrestin activation. This study provides novel insights into the regulatory mechanisms of CB2, which may aid in our understanding of drug tolerance and dependence.

Zusammenfassung in einer weiteren Sprache
Fachgebiet (DDC)
570 Biowissenschaften, Biologie
Schlagwörter
Cannabinoid CB2 receptor, β-arrestin, G protein-coupled receptor kinase
Konferenz
Rezension
undefined / . - undefined, undefined
Forschungsvorhaben
Organisationseinheiten
Zeitschriftenheft
Datensätze
Zitieren
ISO 690PATEL, Monica, Christoph MATTI, Natasha L. GRIMSEY, Daniel F. LEGLER, Jonathan A. JAVITCH, David B. FINLAY, Michelle GLASS, 2022. Delineating the interactions between the cannabinoid CB2 receptor and its regulatory effectors; β-arrestins and G protein-coupled receptor kinases. In: British Journal of Pharmacology (BJP). Wiley. 2022, 179(10), pp. 2223-2239. ISSN 0366-0826. eISSN 1476-5381. Available under: doi: 10.1111/bph.15748
BibTex
@article{Patel2022-05Delin-55750,
  year={2022},
  doi={10.1111/bph.15748},
  title={Delineating the interactions between the cannabinoid CB2 receptor and its regulatory effectors; β-arrestins and G protein-coupled receptor kinases},
  number={10},
  volume={179},
  issn={0366-0826},
  journal={British Journal of Pharmacology (BJP)},
  pages={2223--2239},
  author={Patel, Monica and Matti, Christoph and Grimsey, Natasha L. and Legler, Daniel F. and Javitch, Jonathan A. and Finlay, David B. and Glass, Michelle}
}
RDF
<rdf:RDF
    xmlns:dcterms="http://purl.org/dc/terms/"
    xmlns:dc="http://purl.org/dc/elements/1.1/"
    xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#"
    xmlns:bibo="http://purl.org/ontology/bibo/"
    xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#"
    xmlns:foaf="http://xmlns.com/foaf/0.1/"
    xmlns:void="http://rdfs.org/ns/void#"
    xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > 
  <rdf:Description rdf:about="https://kops.uni-konstanz.de/server/rdf/resource/123456789/55750">
    <dc:contributor>Legler, Daniel F.</dc:contributor>
    <dcterms:abstract xml:lang="eng">Background and Purpose&lt;br /&gt;The cannabinoid CB&lt;sub&gt;2&lt;/sub&gt; receptor (CB&lt;sub&gt;2&lt;/sub&gt;) is a promising therapeutic target for modulating inflammation. However, little is known surrounding the mechanisms underpinning CB&lt;sub&gt;2&lt;/sub&gt; desensitisation and regulation, particularly the role of G protein-coupled receptor kinases (GRKs). Here, we evaluated the role of six GRK isoforms in β-arrestin recruitment to CB&lt;sub&gt;2&lt;/sub&gt;. Mutagenesis of several distal C-terminal aspartic acid residues was also performed in an attempt to delineate additional structural elements involved in the regulation of CB&lt;sub&gt;2&lt;/sub&gt;.&lt;br /&gt;&lt;br /&gt;Experimental Approach&lt;br /&gt;In CB&lt;sub&gt;2&lt;/sub&gt;-expressing HEK 293 cells, β-arrestin translocation was measured using real-time BRET assays. G protein dissociation BRET assays were performed to assess the activation and desensitisation of CB&lt;sub&gt;2&lt;/sub&gt; in the presence of β-arrestin 2.&lt;br /&gt;&lt;br /&gt;Key Results&lt;br /&gt;Overexpression of GRK isoforms 1-6 failed to considerably improve translocation of either β-arrestin 1 or β-arrestin 2 to CB&lt;sub&gt;2&lt;/sub&gt;. Consistent with this, inhibition of endogenous GRK2/3 did not substantially reduce β-arrestin 2 translocation. Mutagenesis of C-terminal aspartic acid residues resulted in attenuation of β-arrestin 2 translocation, which translated to a reduction in desensitisation of G protein activation.&lt;br /&gt;&lt;br /&gt;Conclusion and Implications&lt;br /&gt;Our findings suggest that CB&lt;sub&gt;2&lt;/sub&gt; does not adhere to the classical GPCR regulatory paradigm, entailing GRK- and β-arrestin-mediated desensitisation. Instead, C-terminal aspartic acid residues may act as phospho-mimics to induce β-arrestin activation. This study provides novel insights into the regulatory mechanisms of CB&lt;sub&gt;2&lt;/sub&gt;, which may aid in our understanding of drug tolerance and dependence.</dcterms:abstract>
    <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dc:contributor>Matti, Christoph</dc:contributor>
    <dc:creator>Grimsey, Natasha L.</dc:creator>
    <dc:contributor>Patel, Monica</dc:contributor>
    <dc:creator>Matti, Christoph</dc:creator>
    <dcterms:title>Delineating the interactions between the cannabinoid CB2 receptor and its regulatory effectors; β-arrestins and G protein-coupled receptor kinases</dcterms:title>
    <dc:creator>Finlay, David B.</dc:creator>
    <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/55750/1/Patel_2-85euuab87s7w2.pdf"/>
    <dc:creator>Javitch, Jonathan A.</dc:creator>
    <dc:creator>Glass, Michelle</dc:creator>
    <dc:rights>terms-of-use</dc:rights>
    <dcterms:rights rdf:resource="https://rightsstatements.org/page/InC/1.0/"/>
    <dc:language>eng</dc:language>
    <dcterms:issued>2022-05</dcterms:issued>
    <foaf:homepage rdf:resource="http://localhost:8080/"/>
    <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/55750"/>
    <dc:creator>Legler, Daniel F.</dc:creator>
    <dc:creator>Patel, Monica</dc:creator>
    <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/55750/1/Patel_2-85euuab87s7w2.pdf"/>
    <dc:contributor>Finlay, David B.</dc:contributor>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2021-12-03T08:12:52Z</dc:date>
    <dc:contributor>Glass, Michelle</dc:contributor>
    <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/>
    <dc:contributor>Javitch, Jonathan A.</dc:contributor>
    <dc:contributor>Grimsey, Natasha L.</dc:contributor>
    <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2021-12-03T08:12:52Z</dcterms:available>
  </rdf:Description>
</rdf:RDF>
Interner Vermerk
xmlui.Submission.submit.DescribeStep.inputForms.label.kops_note_fromSubmitter
Kontakt
URL der Originalveröffentl.
Prüfdatum der URL
Prüfungsdatum der Dissertation
Finanzierungsart
Kommentar zur Publikation
Allianzlizenz
Corresponding Authors der Uni Konstanz vorhanden
Internationale Co-Autor:innen
Universitätsbibliographie
Ja
Begutachtet
Ja
Diese Publikation teilen