Psychiatry related information on RAPGEF4

• We first became interested in EPAC when we discovered that the expression levels of both EPAC1 and EPAC2 were altered in those regions of the brain associated with Alzheimer's disease [McPhee, Breslin, Kewney, MacKenzie, Cooreman, Gibson and Hammond (2004) International Patent number WO 2004/096199 A2] [1].

High impact information on RAPGEF4

• Structural analysis of the cAMP-binding domains of Epac2 has identified a unifying mechanism for how cAMP activates proteins, and the design and synthesis of an Epac-specific cAMP analogue has paved the way for future discoveries [2].
• The RAP1 guanine nucleotide exchange factor Epac2 couples cyclic AMP and Ras signals at the plasma membrane [3].
• Whereas translocation of Epac2 was not mimicked by challenge with epidermal growth factor alone, costimulation with forskolin, prostaglandin E2, or an Epac-selective cyclic AMP analog-induced rapid relocation of GFP-Epac2 but not -Epac1 to the plasma membrane in a Ras-dependent manner [3].
• This domain specifically bound Ras-GTP, enabling oncogenic Ras to translocate Epac2 from the cytosol to the plasma membrane [3].
• Localization of cAMP-GEFII overlaps with that of Rim2 in plasma membrane of insulin-secreting MIN6 cells [4].

Biological context of RAPGEF4

• Affinity measurements show that this distal cAMP binding domain (the A-site) binds cAMP with much lower affinity than the cAMP binding domain proximal to the catalytic domain (the B-site), which is present in both Epac1 and Epac2 [5].
• Human EPAC2 has at least 31 exons and is mapped to human chromosome 2q31 [6].
• Here we clone the gene EPAC2, encoding cAMP-GEFII, from a human liver cDNA library [6].
• Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene [7].
• The Epac family of cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs, also known as Epac1 and Epac2) mediate stimulatory actions of the second messenger cAMP on insulin secretion from pancreatic beta cells [8].

Anatomical context of RAPGEF4

• We found that endogenous EPAC2 is also immunolocalized with LC2 in PC12 cells [9].
• In contrast, protein level of only Epac-2 (P<.001) but not Epac-1 (P = .89) was significantly increased in prefrontal cortex and hippocampus of these subjects [10].
• Epac2 and Rap2 were detected in hamster spermatozoa using immunoblotting [11].

Associations of RAPGEF4 with chemical compounds

• Thus, Epac2 can respond to costimulation by agonists that jointly elevate Ras-GTP and cyclic AMP levels, activating a specific pool of Rap1 at the plasma membrane [3].
• In the beta-cell, cAMP binds and modulates activities of both protein kinase A and cAMP-regulated guanine nucleotide exchange factor II, thereby enhancing glucose-dependent insulin secretion [12].

Physical interactions of RAPGEF4

• We subsequently developed a novel, high-throughput screen based on the displacement of [3H]cAMP from the EPAC cAMP-binding site and identified small molecule hits from the Scottish Biomedical Lead Generation Library. These compounds selectively bind to the cAMP-binding sites of EPAC1 and EPAC2 and are structurally dissimilar to cAMP [1].

Other interactions of RAPGEF4

• In addition to the cAMP binding domains, both Epac1 and Epac2 have a DEP domain [5].
• Further studies are needed to clarify the contribution of cAMP-GEFII gene variants to autism susceptibility [7].
• Among these 1,050 transcripts were cAMP-GEFII and TRB3, which have increased and decreased mRNA abundance, respectively [13].

References