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Molecular Pharmacology

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Rapid CommunicationMinireview

The G Protein α Chaperone Ric-8 as a Potential Therapeutic Target

Makaía M. Papasergi, Bharti R. Patel and Gregory G. Tall
Molecular Pharmacology January 2015, 87 (1) 52-63; DOI: https://doi.org/10.1124/mol.114.094664
Makaía M. Papasergi
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York
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Bharti R. Patel
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York
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Gregory G. Tall
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York
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Abstract

Resistance to inhibitors of cholinesterase (Ric-8)A and Ric-8B are essential genes that encode positive regulators of heterotrimeric G protein α subunits. Controversy persists surrounding the precise way(s) that Ric-8 proteins affect G protein biology and signaling. Ric-8 proteins chaperone nucleotide-free Gα-subunit states during biosynthetic protein folding prior to G protein heterotrimer assembly. In organisms spanning the evolutionary window of Ric-8 expression, experimental perturbation of Ric-8 genes results in reduced functional abundances of G proteins because G protein α subunits are misfolded and degraded rapidly. Ric-8 proteins also act as Gα-subunit guanine nucleotide exchange factors (GEFs) in vitro. However, Ric-8 GEF activity could strictly be an in vitro phenomenon stemming from the ability of Ric-8 to induce partial Gα unfolding, thereby enhancing GDP release. Ric-8 GEF activity clearly differs from the GEF activity of G protein–coupled receptors (GPCRs). G protein βγ is inhibitory to Ric-8 action but obligate for receptors. It remains an open question whether Ric-8 has dual functions in cells and regulates G proteins as both a molecular chaperone and GEF. Clearly, Ric-8 has a profound influence on heterotrimeric G protein function. For this reason, we propose that Ric-8 proteins are as yet untested therapeutic targets in which pharmacological inhibition of the Ric-8/Gα protein–protein interface could serve to attenuate the effects of disease-causing G proteins (constitutively active mutants) and/or GPCR signaling. This minireview will chronicle the understanding of Ric-8 function, provide a comparative discussion of the Ric-8 molecular chaperoning and GEF activities, and support the case for why Ric-8 proteins should be considered potential targets for development of new therapies.

Footnotes

    • Received July 10, 2014.
    • Accepted October 14, 2014.
  • This work was supported by grants from the National Institutes of Health [R01-GM088242], an Institutional Ruth L. Kirschstein National Research Service Award [GM068411], and a grant to the University of Rochester School of Medicine and Dentistry from the Howard Hughes Medical Institute through the Med into Grad Initiative.

  • dx.doi.org/10.1124/mol.114.094664.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 87 (1)
Molecular Pharmacology
Vol. 87, Issue 1
1 Jan 2015
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Rapid CommunicationMinireview

The G Protein α Chaperone Ric-8

Makaía M. Papasergi, Bharti R. Patel and Gregory G. Tall
Molecular Pharmacology January 1, 2015, 87 (1) 52-63; DOI: https://doi.org/10.1124/mol.114.094664

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Rapid CommunicationMinireview

The G Protein α Chaperone Ric-8

Makaía M. Papasergi, Bharti R. Patel and Gregory G. Tall
Molecular Pharmacology January 1, 2015, 87 (1) 52-63; DOI: https://doi.org/10.1124/mol.114.094664
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  • Article
    • Abstract
    • Introduction
    • Ric-8 Regulation of G Protein Abundance
    • Ric-8 as a G Protein α Subunit Guanine Nucleotide Exchange Factor
    • How Does Ric-8 Regulate Gαi/o Protein-Controlled Mitotic Spindle Positioning?
    • Should Ric-8 Be a Therapeutic Target for Diseases Driven by Mutant Gα Subunits or to Attenuate GPCR Signaling?
    • Therapeutic Chaperone Inhibition Is an Established Paradigm
    • Defining the Ric-8/Gα PPI and Targeting It for Inhibition
    • Summary
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