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The G ProteinαChaperone Ric-8 as a Potential Therapeutic Target
- Source :
- Molecular Pharmacology. 87:52-63
- Publication Year :
- 2014
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2014.
-
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.
- Subjects :
- Pharmacology
G protein-coupled receptor kinase
GTPase-activating protein
G protein
Biology
Cell biology
G beta-gamma complex
Biochemistry
GTP-Binding Proteins
hemic and lymphatic diseases
Heterotrimeric G protein
G12/G13 alpha subunits
Animals
Guanine Nucleotide Exchange Factors
Humans
Molecular Medicine
cAMP-dependent pathway
Minireview
Enzyme Inhibitors
Molecular Chaperones
Signal Transduction
G protein-coupled receptor
Subjects
Details
- ISSN :
- 15210111 and 0026895X
- Volume :
- 87
- Database :
- OpenAIRE
- Journal :
- Molecular Pharmacology
- Accession number :
- edsair.doi.dedup.....fff00267e1204f4123e4849ab9c92d8f