RAPGEF4

Last update 23 Jan 2025

Basic Info

Synonyms

exchange protein directly activated by cAMP 2, cAMP-GEFII, cAMP-regulated guanine nucleotide exchange factor II

+ [9]

Introduction

Guanine nucleotide exchange factor (GEF) for RAP1A, RAP1B and RAP2A small GTPases that is activated by binding cAMP. Seems not to activate RAB3A. Involved in cAMP-dependent, PKA-independent exocytosis through interaction with RIMS2 (By similarity).

100 Clinical Results associated with RAPGEF4

100 Translational Medicine associated with RAPGEF4

0 Patents (Medical) associated with RAPGEF4

376

Literatures (Medical) associated with RAPGEF4

01 Nov 2025·Neural Regeneration Research

Targeting Epac2 and GluA3-containing AMPARs: a novel therapeutic strategy for Alzheimer’s disease

Article

Author: Schmidt, Martina ; Zhang, Tong

Alzheimer′s disease (AD) is a neurodegenerative disease that manifests progressive decline in memory and cognition.In the early stage of AD, memory retrieval is impaired preceding memory acquisition and consolidation (Roy et al., 2016).Prior to the onset of symptoms, pathol. amyloid-β (Aβ) plagues and tau protein tangles accumulate in extracellular and intracellular spaces, resp., leading to neurodegeneration.Among these hallmark pathologies, Aβ is proposed to be the primary etiol. by triggering a cascade of pathogenic events, including neuroinflammation, oxidative stress, tau hyperphosphorylation, synaptic/neuronal dysfunction, and neuronal death (Zhang et al., 2023b).

15 Feb 2025·International Journal of Cancer

Tumor‐derived lactic acid promotes acetylation of histone H3K27 and differentiation of IL‐10‐producing regulatory B cells through direct and indirect signaling pathways

Article

Author: Hara, Isao ; Hashimoto, Shinichi ; Akazawa, Takashi ; Katayama, Kei‐ichi ; Inoue, Norimitsu ; Iwabuchi, Sadahiro ; Baba, Takashi ; Kusumoto, Hiroki ; Yamashita, Shimpei ; Muraoka, Satoshi ; Kohjimoto, Yasuo

AbstractTumor cells are known to enhance glycolysis, even under normoxic conditions, via the Warburg effect, producing excess lactic acid in the tumor microenvironment. Lactic acid enhances the IL‐23/IL‐17 pathway and induces chronic inflammation. The acidic microenvironment formed by lactic acid suppresses immune cell proliferation and activation. In the present study, we clarified that lactic acid had two novel activities for immune cells. First, lactic acid specifically enhanced acetylation at lysine 27 of histone H3 (H3K27ac) in splenic B cells and monocytes/macrophages, and this epigenetically up‐regulates the expression of genes. Acetylation and methylation of other residues of histone H3 were rarely induced. Second, lactic acid induced a particularly‐marked enhancement of Il10 gene expression in B cells, leading to an increase in IL‐10‐producing regulatory B (Breg) cells. Furthermore, two pathways should be involved in both the enhancement of H3K27ac and the induction of Breg cells by lactic acid: a direct pathway that enhances the CD40 signal in B cells, and an indirect pathway that affects B cells by activating the exchange protein directly activated by cAMP (EPAC) 1/2 in non‐B cells. In tumor‐bearing mice, the levels of H3K27ac of tumor‐infiltrating B cells were significantly higher than splenic B cells and were suppressed by intraperitoneal injection of the EPAC1/2 inhibitor. In conclusion, tumor‐derived lactic acid increases H3K27ac and IL‐10‐producing Breg cells, causing the suppression of anti‐tumor immunity.

01 Oct 2024·Neuropharmacology

The PDE4 inhibitor apremilast modulates ethanol responses in Gabrb1-S409A knock-in mice via PKA-dependent and independent mechanisms

Article

Author: Homanics, Gregg E ; Shawlot, William ; Blednov, Yuri A ; Messing, Robert O ; Mayfield, Jody ; Moss, Stephen J ; Smalley, Joshua L ; Osterndorff-Kahanek, Elizabeth A ; Mason, Sonia

We previously showed that the PDE4 inhibitor apremilast reduces ethanol consumption in mice by protein kinase A (PKA) and GABAergic mechanisms. Preventing PKA phosphorylation of GABA_A β3 subunits partially blocked apremilast-mediated decreases in drinking. Here, we produced Gabrb1-S409A mice to render GABA_A β1 subunits resistant to PKA-mediated phosphorylation. Mass spectrometry confirmed the presence of the S409A mutation and lack of changes in β1 subunit expression or phosphorylation at other residues. β1-S409A male and female mice did not differ from wild-type C57BL/6J mice in expression of Gabrb1, Gabrb2, or Gabrb3 subunits or in behavioral characteristics. Apremilast prolonged recovery from ethanol ataxia to a greater extent in Gabrb1-S409A mice but prolonged recovery from zolpidem and propofol to a similar extent in both genotypes. Apremilast shortened recovery from diazepam ataxia in wild-type but prolonged recovery in Gabrb1-S409A mice. In wild-type mice, the PKA inhibitor H89 prevented apremilast modulation of ataxia by ethanol and diazepam, but not by zolpidem. In Gabrb1-S409A mice, inhibiting PKA or EPAC2 (exchange protein directly activated by cAMP) partially reversed apremilast potentiation of ethanol, diazepam, and zolpidem ataxia. Apremilast prevented acute tolerance to ethanol ataxia in both genotypes, but there were no genotype differences in ethanol consumption before or after apremilast. In contrast to results in Gabrb3-S408A/S409A mice, PKA phosphorylation of β1-containing GABA_A receptors is not required for apremilast's effects on acute tolerance or on ethanol consumption but is required for its ability to decrease diazepam intoxication. Besides PKA we identified EPAC2 as an additional cAMP-dependent mechanism by which apremilast regulates responses to GABAergic drugs.

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RAPGEF4

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