This review focuses on one family of the known cAMP receptors, the exchange proteins directly activated by cAMP (EPACs), also known as the cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs). Although EPAC proteins are fairly new additions to the growing list of cAMP effectors, and relatively "young" in the cAMP discovery timeline, the significance of an EPAC presence in different cell systems is extraordinary. The study of EPACs has considerably expanded the diversity and adaptive nature of cAMP signaling associated with numerous physiological and pathophysiological responses. This review comprehensively covers EPAC protein functions at the molecular, cellular, physiological, and pathophysiological levels; and in turn, the applications of employing EPAC-based biosensors as detection tools for dissecting cAMP signaling and the implications for targeting EPAC proteins for therapeutic development are also discussed.

Vascular smooth muscle cell (VSMC) activation in response to injury plays an important role in the development of vascular proliferative diseases, including restenosis and atherosclerosis. The aims of this study were to ascertain the physiological functions of exchange proteins directly activated by cAMP isoform 1 (Epac1) in VSMC and to evaluate the potential of Epac1 as therapeutic targets for neointima formation during vascular remodeling. In a mouse carotid artery ligation model, genetic knockdown of the Epac1 gene led to a significant reduction in neointima obstruction in response to vascular injury. Pharmacologic inhibition of Epac1 with an Epac specific inhibitor, ESI-09, phenocopied the effects of Epac1 null by suppressing neointima formation and proliferative VSMC accumulation in neointima area. Mechanistically, Epac1 deficient VSMCs exhibited lower level of PI3K/AKT signaling and dampened response to PDGF-induced mitochondrial fission and reactive oxygen species levels. Our studies indicate that Epac1 plays important roles in promoting VSMC proliferation and phenotypic switch in response to vascular injury, therefore, representing a therapeutic target for vascular proliferative diseases.

h Epacs (exchange proteins directly activated by cyclic AMP [cAMP]) act as downstream effectors of cAMP and play important roles in energy balance and glucose homeostasis. While global deletion of Epac1 in mice leads to heightened leptin sensitivity in the hypothalamus and partial protection against high-fat diet (HFD)-induced obesity, the physiological functions of Epac1 in white adipose tissue (WAT) has not been explored. Here, we report that adipose tissue-specific Epac1 knockout (AEKO) mice are more prone to HFD-induced obesity, with increased food intake, reduced energy expenditure, and impaired glucose tolerance. Despite the fact that AEKO mice on HFD display increased body weight, these mice have decreased circulating leptin levels compared to their wild-type littermates. In vivo and in vitro analyses further reveal that suppression of Epac1 in WAT decreases leptin mRNA expression and secretion by inhibiting cAMP response element binding (CREB) protein and AKT phosphorylation, respectively. Taken together, our results demonstrate that Epac1 plays an important role in regulating energy balance and glucose homeostasis by promoting leptin expression and secretion in WAT.O besity has become a severe public health problem, and its prevalence has increased dramatically since the 1970s. In the United States, more than one-third of adults and approximately 17% of children are obese, defined as a body mass index (BMI) of 30 or above. It is projected that by 2030, more than 50% of the U.S. population will be obese (1). This dire outlook led the American Medical Association to officially recognize obesity as a disease. In addition to its direct health problems, obesity is also closely associated with other major human diseases, such as diabetes and cardiovascular diseases (2, 3). Despite its overwhelming prevalence and major health burdens, we know little about the molecular etiology of obesity and even less about its cures. At the physiology level, one major factor leading to the development of obesity is a chronic imbalance of energy homeostasis, which results in the accumulation of the excessive energy intake as fat in tissues, especially in adipocytes.Adipose tissue not only is the main reservoir for fat storage but also is an important endocrine organ that secrets various adiposederived hormones, called adipokines. As one of the most important and widely studied adipokines, leptin plays a critical role in energy balance, mainly by acting on receptors in the arcuate nucleus of the hypothalamus to suppress appetite and to increase energy expenditure (4, 5). While the circulating leptin level is proportional to the total body fat mass in rodents and human, in obese patients a reduced sensitivity to leptin leads to a failure in suppressing food intake despite increased fat stores and blood leptin levels. This apparent condition of leptin resistance is one major driver in developing obesity (6).Recent studies have implicated the involvement of Epac1 (exchange protein directly activated by cyclic AMP [cAMP])-mediated...