The psychosis risk gene RBM12 encodes a novel repressor of GPCR/cAMP signal transduction II
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE229254 | GEO | 2023/08/02
REPOSITORIES: GEO
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Project description:A deeper understanding of the regulation of G protein-coupled receptors (GPCRs) and their associated downstream cascades will provide critical insights into how these pathways shape human physiology and disease, and could yield novel therapeutic targets. Here, we validate and characterize RNA-binding motif 12 (Rbm12) as a repressor of GPCR/cAMP signaling. We established Rbm12 CRISPR KO HEK293 cells using two independent gRNAs and human iPSC-derived neurons (iNeuron) depleted of Rbm12 via CRISPR interference. Then, we performed basal gene expression profiling (HEK293) and basal + beta-2-adrenergic receptor induced (1 hour of 1 uM Isoproterenol) conditions (neurons).
2023-08-02 | GSE219195 | GEO
Project description:RBM12 is a high-penetrance risk factor for familial schizophrenia and psychosis, yet its precise cellular functions and the pathways to which it belongs are not known. We utilize two complementary models, HEK293 cells and human iPSC-derived neurons, and delineate RBM12 as a novel repressor of the G protein-coupled receptor/cyclic AMP/protein kinase A (GPCR/cAMP/PKA) signaling axis. We establish that loss of RBM12 leads to hyperactive cAMP production and increased PKA activity as well as altered neuronal transcriptional responses to GPCR stimulation. Notably, the cAMP and transcriptional signaling steps are subject to discrete RBM12-dependent regulation. We further demonstrate that the two RBM12 truncating variants linked to familial psychosis impact this interplay, as the mutants fail to rescue GPCR/cAMP signaling hyperactivity in cells depleted of RBM12. Lastly, we present a mechanism underlying the impaired signaling phenotypes. In agreement with its activity as an RNA-binding protein, loss of RBM12 leads to altered gene expression, including that of multiple effectors of established significance within the receptor pathway. Specifically, the abundance of adenylyl cyclases, phosphodiesterase isoforms, and PKA regulatory and catalytic subunits is impacted by RBM12 depletion. We note that these expression changes are fully consistent with the entire gamut of hyperactive signaling outputs. In summary, the current study identifies a previously unappreciated role for RBM12 in the context of the GPCR/cAMP pathway that could be explored further as a tentative molecular mechanism underlying the functions of this factor in neuronal physiology and pathophysiology.
| S-EPMC9882185 | biostudies-literature
Project description:The psychosis risk gene RBM12 encodes a novel repressor of GPCR/cAMP signal transduction
| PRJNA907376 | ENA
Project description:The psychosis risk gene RBM12 encodes a novel repressor of GPCR/cAMP signal transduction II
| PRJNA953642 | ENA
Project description:G protein-coupled receptors in intracellular organelles can be activated in response to membrane permeant ligands, which contributes to the diversity and specificity of agonist action. The opioid receptors (ORs) provide a striking example, where small molecule opioid drugs activate ORs in the Golgi apparatus within seconds of drug addition. To date, our knowledge on the signaling of intracellular GPCRs remains incomplete and it is unknown if the downstream events triggered by ORs in plasma membrane and Golgi apparatus differ. To address this gap, we analyzed OR-mediated gene expression changes upon treatment with impermeant peptide ligand DPDPE, permeant ligand SNC80 or ICI-SNC80 (Golgi-restricted signaling). We show that DOR activation in the Golgi does not trigger any gene transcription at these two time points as compare to plasma membrane receptors. The study delineates OR signal transduction with unprecedented resolution and reveals that the subcellular location defines the signaling effect promoted by opioid drugs.
2023-04-24 | GSE221762 | GEO
Project description:Disruption of Ras/cAMP signaling by perturbation of pathway elements and controlled cAMP concentration. All cultures grown in SC medium. Keywords: other
2005-10-01 | GSE2927 | GEO
Project description:G protein-coupled receptors in intracellular organelles can be activated in response to membrane permeant ligands, which contributes to the diversity and specificity of agonist action. The opioid receptors (ORs) provide a striking example, where small molecule opioid drugs activate ORs in the Golgi apparatus within seconds of drug addition. To date, our knowledge on the signaling of intracellular GPCRs remains incomplete and it is unknown if the downstream events triggered by ORs in plasma membrane and Golgi apparatus differ. To address this gap, we analyzed OR-mediated phosphorylation changes in cells treated with SNC80 (signaling control) or ICI-SNC80 (Golgi-restricted signaling) for 5 min or 25 min. We show that OR activation in the plasma membrane or Golgi apparatus have strikingly different downstream effects on protein phosphorylation. The study delineates OR signal transduction with unprecedented resolution and reveals that the subcellular location defines the signaling effect promoted by opioid drugs.
2023-04-25 | PXD038921 | Pride
Project description:Subcellular location defines GPCR signal transduction
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Project description:Our study demonstrates direct evidence that canonical cAMP/Creb signaling through adrenergic receptors can regulate HFSC activation and the hair cycle. This intracellular signaling circuit connects to downstrean glycolytic metabolism processes which have been previously shown to stimulate HSFC activation.
2021-04-30 | GSE173591 | GEO
Project description:G protein-coupled receptors (GPCRs) are seven integral transmembrane proteins that are the primary targets of almost 30% of approved drugs and continue to represent a major focus of pharmaceutical research. All of GPCR targeted medicines were discovered by classical medicinal chemistry approaches. After the first GPCR crystal structures were determined, the docking screens using these structures lead to discovery of more novel and potent ligands. There are over 360 pharmaceutically relevant GPCRs in the human genome and to date about only 30 of structures have been determined. For these reasons, computational techniques such as homology modeling and molecular dynamics simulations have proven their usefulness to explore the structure and function of GPCRs. Furthermore, structure-based drug design and in silico screening (High Throughput Docking) are still the most common computational procedures in GPCRs drug discovery. Moreover, ligand-based methods such as three-dimensional quantitative structure-selectivity relationships, are the ideal molecular modeling approaches to rationalize the activity of tested GPCR ligands and identify novel GPCR ligands. In this review, we discuss the most recent advances for the computational approaches to effectively guide selectivity and affinity of ligands. We also describe novel approaches in medicinal chemistry, such as the development of biased agonists, allosteric modulators, and bivalent ligands for class A GPCRs. Furthermore, we highlight some knockout mice models in discovering biased signaling selectivity.
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