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Molecular Pharmacology

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Research ArticleMinireview

Roles of Receptor Phosphorylation and Rab Proteins in G Protein-Coupled Receptor Function and Trafficking

Juan Carlos Martínez-Morales, M. Teresa Romero-Ávila, Guadalupe Reyes-Cruz and Jesús Adolfo García-Sáinz
Molecular Pharmacology March 2022, 101 (3) 144-153; DOI: https://doi.org/10.1124/molpharm.121.000429
Juan Carlos Martínez-Morales
Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México, México (J.C.M.-M., M.T.R.-Á, J.A.G.-S.) and Departamento de Biología Celular, Centro de Investigación y Estudios Avanzados, Avanzados-Instituto Politécnico Nacional, Ciudad de México, México (G.R.-C.)
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M. Teresa Romero-Ávila
Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México, México (J.C.M.-M., M.T.R.-Á, J.A.G.-S.) and Departamento de Biología Celular, Centro de Investigación y Estudios Avanzados, Avanzados-Instituto Politécnico Nacional, Ciudad de México, México (G.R.-C.)
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Guadalupe Reyes-Cruz
Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México, México (J.C.M.-M., M.T.R.-Á, J.A.G.-S.) and Departamento de Biología Celular, Centro de Investigación y Estudios Avanzados, Avanzados-Instituto Politécnico Nacional, Ciudad de México, México (G.R.-C.)
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Jesús Adolfo García-Sáinz
Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México, México (J.C.M.-M., M.T.R.-Á, J.A.G.-S.) and Departamento de Biología Celular, Centro de Investigación y Estudios Avanzados, Avanzados-Instituto Politécnico Nacional, Ciudad de México, México (G.R.-C.)
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Abstract

The G protein-coupled receptors form the most abundant family of membrane proteins and are crucial physiologic players in the homeostatic equilibrium, which we define as health. They also participate in the pathogenesis of many diseases and are frequent targets of therapeutic intervention. Considering their importance, it is not surprising that different mechanisms regulate their function, including desensitization, resensitization, internalization, recycling to the plasma membrane, and degradation. These processes are modulated in a highly coordinated and specific way by protein kinases and phosphatases, ubiquitin ligases, protein adaptors, interaction with multifunctional complexes, molecular motors, phospholipid metabolism, and membrane distribution. This review describes significant advances in the study of the regulation of these receptors by phosphorylation and endosomal traffic (where signaling can take place); we revisited the bar code hypothesis and include two additional observations: 1) that different phosphorylation patterns seem to be associated with internalization and endosome sorting for recycling or degradation, and 2) that, surprisingly, phosphorylation of some G protein-coupled receptors appears to be required for proper receptor insertion into the plasma membrane.

SIGNIFICANCE STATEMENT G protein-coupled receptor phosphorylation is an early event in desensitization/signaling switching, endosomal traffic, and internalization. These events seem crucial for receptor responsiveness, cellular localization, and fate (recycling/degradation) with important pharmacological/therapeutic implications. Phosphorylation sites vary depending on the cells in which they are expressed and on the stimulus that leads to such covalent modification. Surprisingly, evidence suggests that phosphorylation also seems to be required for proper insertion into the plasma membrane for some receptors.

Footnotes

    • Received October 10, 2021.
    • Accepted December 22, 2021.
  • This work was partially supported by a grant from Consejo Nacional de Ciencia y Tecnologia (Fronteras 6676) and DGAPA [IN201221].

  • https://doi.org/10.1124/molpharm.121.000429.

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 101 (3)
Molecular Pharmacology
Vol. 101, Issue 3
1 Mar 2022
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Research ArticleMinireview

G Protein-Coupled Receptor Phosphorylation and Rab Proteins

Juan Carlos Martínez-Morales, M. Teresa Romero-Ávila, Guadalupe Reyes-Cruz and Jesús Adolfo García-Sáinz
Molecular Pharmacology March 1, 2022, 101 (3) 144-153; DOI: https://doi.org/10.1124/molpharm.121.000429

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Research ArticleMinireview

G Protein-Coupled Receptor Phosphorylation and Rab Proteins

Juan Carlos Martínez-Morales, M. Teresa Romero-Ávila, Guadalupe Reyes-Cruz and Jesús Adolfo García-Sáinz
Molecular Pharmacology March 1, 2022, 101 (3) 144-153; DOI: https://doi.org/10.1124/molpharm.121.000429
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  • Article
    • Abstract
    • Introduction
    • GPCR Desensitization and Posttranslational Modifications Involved
    • Receptor Phosphorylation, the Barcode Hypothesis, and β-Arrestins
    • Does GPCR Phosphorylation Always Result in Internalization?
    • Rab Proteins
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