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Last update 08 May 2025

RIC8B

Last update 08 May 2025

Basic Info

Synonyms

Brain synembryn, FLJ10620, hSyn

+ [5]

Introduction

Chaperone that specifically binds and folds nascent G(s) G-alpha proteins (GNAS and GNAL) prior to G protein heterotrimer formation, promoting their association with the plasma membrane (By similarity). Also acts as a guanine nucleotide exchange factor (GEF) for G(s) proteins by stimulating exchange of bound GDP for free GTP (By similarity). Acts as an important component for odorant signal transduction by mediating GNAL (G(olf)-alpha) folding, thereby promoting-dependent cAMP accumulation in olfactory sensory neurons (By similarity).

Drugs associated with RIC8B

WO2023201277

Patent Mining

Target

RIC8B

Mechanism-

Active Org.

RegenxBio, Inc.

Originator Org.

RegenxBio, Inc.

Active Indication

Nervous System Diseases

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

CN114606264

Patent Mining

Target

RIC8B

Mechanism-

Active Org.

China Three Gorges University

Originator Org.

China Three Gorges University

Active Indication

Infectious Diseases [+2]

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with RIC8B

100 Translational Medicine associated with RIC8B

0 Patents (Medical) associated with RIC8B

117

Literatures (Medical) associated with RIC8B

01 Jun 2025·Molecular Therapy Methods & Clinical Development

Targeted spiral ganglion neuron degeneration in parvalbumin-Cre neonatal mice

Article

Author: Shibata, Seiji B ; Cutri, Raffaello M ; Lin, Joshua S ; Nguyen, Nhi V ; Parikh, Miti J

The spiral ganglion neurons (SGNs) are the primary afferent neurons in the cochlea; damage to the SGNs leads to irreversible hearing impairment. Mouse models that allow selective SGN degeneration while sparing other cell types in the cochlea are lacking. Here, we investigated a genetic ablation method of the SGN using a Cre-responsive adeno-associated virus (AAV) vector expressing diphtheria toxin subunit-A (DTA). We microinjected AAV2-retro-FLEX-DTA-mCherry driven by the EF1a or hSYN promoter in neonatal parvalbumin-Cre (PV^Cre) and wild-type strains via the posterior semicircular canal. Apoptotic markers were observed in the degenerating SGNs as early as 3 days. After 1 week, we assessed the SGN cell density, revealing an average degeneration of 60% for AAV-DTA driven by the EF1a promoter and 61% for that driven by the hSYN promoter. By 1 month, injected ears demonstrated a nearly complete loss of SGN, while hair cell morphology was intact. The auditory brain stem response result showed significantly elevated threshold shifts at 1 month, while the distortion-product otoacoustic emissions function remained intact. Furthermore, we show that our method did not effectively ablate SGN in adult PV^Cre mice. We generated a neonatal mouse model with primary SGN degeneration in PV^Cre mice, mimicking auditory neuropathy phenotype using an AAV Cre-dependent expression of DTA.

11 Dec 2024·mBio

RNAseq and targeted metabolomics implicate RIC8 in regulation of energy homeostasis, amino acid compartmentation, and asexual development in Neurospora crassa

Article

Author: Borkovich, Katherine A. ; Halilovic, Lida ; Quinn, Monique ; Carrillo, Alexander J.

ABSTRACT Heterotrimeric G protein signaling pathways control growth and development in eukaryotes. In the multicellular fungus Neurospora crassa , the guanine nucleotide exchange factor RIC8 regulates heterotrimeric Gα subunits. In this study, we used RNAseq and liquid chromatography-mass spectrometry (LC-MS) to profile the transcriptomes and metabolomes of N. crassa wild type, the Gα subunit mutants Δ gna-1 and Δ gna-3 , and Δ ric8 strains. These strains exhibit defects in growth and asexual development (conidiation), with wild-type and Δ gna-1 mutants producing hyphae in submerged cultures, while Δ gna-3 and Δ ric8 mutants develop conidiophores, particularly in the Δ ric8 mutant. RNAseq analysis showed that the Δ gna-1 mutant possesses 159 mis-regulated genes, while Δ gna-3 and Δ ric8 strains have more than 1,000 each. Many of the mis-regulated genes are involved in energy homeostasis, conidiation, or metabolism. LC-MS revealed changes in levels of primary metabolites in the mutants, with several arginine metabolic intermediates impacted in Δ ric8 strains. The differences in metabolite levels could not be fully explained by the expression or activity of pathway enzymes. However, transcript levels for two predicted vacuolar arginine transporters were affected in Δ ric8 mutants. Analysis of arginine and ornithine levels in transporter mutants yielded support for altered compartmentation of arginine and ornithine between the cytosol and vacuole in Δ ric8 strains. Furthermore, we validated previous reports that arginine and ornithine levels are low in wild-type conidia. Our results suggest that RIC8 regulates asexual sporulation in N. crassa at least in part through altered expression of vacuolar transporter genes and the resultant mis-compartmentation of arginine and ornithine. IMPORTANCE Resistance to inhibitors of cholinesterase-8 (RIC8) is an important regulator of heterotrimeric Gα proteins in eukaryotes. In the filamentous fungus Neurospora crassa , mutants lacking ric8 undergo inappropriate asexual development (macroconidiation) during submerged growth. Our work identifies a role for RIC8 in regulating expression of transporter genes that retain arginine and ornithine in the vacuole (equivalent of the animal lysosome) and relates this function to the developmental defect. Arginine is a critical cellular metabolite, both as an amino acid for protein synthesis and as a precursor for an array of compounds, including proline, ornithine, citrulline, polyamines, creatine phosphate, and nitric oxide. These results have broad relevance to human physiology and disease, as arginine modulates immune, vascular, hormonal, and other functions in humans.

01 Aug 2024·Journal of Clinical Investigation

Neomorphic Gαo mutations gain interaction with Ric8 proteins in GNAO1 encephalopathies

Article

Author: Valnohova, Jana ; Katanaev, Vladimir L ; Savitsky, Mikhail ; Kazemzadeh, Arghavan ; Solis, Gonzalo P ; Koval, Alexey

GNAO1 mutated in pediatric encephalopathies encodes the major neuronal G protein Gαo. Of the more than 80 pathogenic mutations, most are single amino acid substitutions spreading across the Gαo sequence. We performed extensive characterization of Gαo mutants, showing abnormal GTP uptake and hydrolysis and deficiencies in binding Gβγ and RGS19. Plasma membrane localization of Gαo was decreased for a subset of mutations that leads to epilepsy; dominant interactions with GPCRs also emerged for the more severe mutants. Pathogenic mutants massively gained interaction with Ric8A and, surprisingly, Ric8B proteins, relocalizing them from cytoplasm to Golgi. Of these 2 mandatory Gα-subunit chaperones, Ric8A is normally responsible for the Gαi/Gαo, Gαq, and Gα12/Gα13 subfamilies, and Ric8B solely responsible for Gαs/Gαolf. Ric8 mediates the disease dominance when engaging in neomorphic interactions with pathogenic Gαo through imbalance of the neuronal G protein signaling networks. As the strength of Gαo-Ric8B interactions correlates with disease severity, our study further identifies an efficient biomarker and predictor for clinical manifestations in GNAO1 encephalopathies. Our work uncovers the neomorphic molecular mechanism of mutations underlying pediatric encephalopathies and offers insights into other maladies caused by G protein malfunctioning and further genetic diseases.

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RIC8B

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