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Exchange proteins directly activated by cAMP (EPACs): Emerging therapeutic targets.

ABSTRACT: Exchange proteins directly activated by cAMP (EPACs) are critical cAMP-dependent signaling pathway mediators. The discovery of EPAC proteins has significantly facilitated understanding on cAMP-dependent signaling pathway and efforts along this line open new avenues for developing novel therapeutics for cancer, diabetes, heart failure, inflammation, infections, neurological disorders and other human diseases. Over the past decade, important progress has been made in the identification of EPAC agonists, antagonists and their biological and pharmacological applications. In this review, we briefly summarize recently reported novel functions of EPACs and the discovery of their small molecule modulators. The challenges and future perspectives are also discussed.

SUBMITTER: Wang P

PROVIDER: S-EPMC5397994 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Exchange proteins directly activated by cAMP (EPACs): Emerging therapeutic targets.

Wang Pingyuan P Liu Zhiqing Z Chen Haiying H Ye Na N Cheng Xiaodong X Zhou Jia J

Bioorganic & medicinal chemistry letters 20170227 8

Exchange proteins directly activated by cAMP (EPACs) are critical cAMP-dependent signaling pathway mediators. The discovery of EPAC proteins has significantly facilitated understanding on cAMP-dependent signaling pathway and efforts along this line open new avenues for developing novel therapeutics for cancer, diabetes, heart failure, inflammation, infections, neurological disorders and other human diseases. Over the past decade, important progress has been made in the identification of EPAC ago ...[more]

PMID: 28283242

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Project description:Previous studies demonstrate essential roles for the exchange proteins directly activated by cAMP 1 and 2 (Epac1 and Epac2; here collectively referred to as Epac) in the brain. In the hippocampus, Epac contributes to the control of neuronal growth and differentiation and has been implicated in memory and learning as well as in anxiety and depression. In the present study we address the hypothesis that Epac affects hippocampal cellular responses to acute restraint stress. Stress causes activation of the hypothalamus-pituitary-adrenal (HPA)-axis, and glucocorticoid receptor (GR) signaling is essential for proper feedback regulation of the stress response, both in the brain and along the HPA axis. In the hippocampus, GR expression is regulated by cAMP and the brain enriched micro RNA miR-124. Epac has been associated with miR-124 expression in hippocampal neurons, but not in regulation of GR. We report that hippocampal expression of Epac1 and Epac2 increased in response to acute stress in female wild type mice. In female mice genetically deleted for Epac, nuclear translocation of GR in response to restraint stress was significantly delayed, and moreover, miR-124 expression was decreased in these mice. Male mice lacking Epac also showed abnormalities in miR-124 expression, but the phenotype was less profound than in females. Serum corticosterone levels were slightly altered immediately after stress in both male and female mice deleted for Epac. The presented data indicate that Epac1 and Epac2 are involved in controlling cellular responses to acute stress in the mouse hippocampus and provide novel insights into the underlying transcriptional and signaling networks. Interestingly, we observe sex specific differences when Epac is deleted. As the incidence and prevalence of stress-related diseases are higher in women than in men, the Epac knockout models might serve as genetic tools to further elucidate the cellular mechanisms underlying differences between male and female with regard to regulation of stress.

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Exchange proteins directly activated by cAMP (EPACs): Emerging therapeutic targets.

Publications

Exchange proteins directly activated by cAMP (EPACs): Emerging therapeutic targets.

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