One possible pitfall of using EPAC activators in

One possible pitfall of using EPAC2 activators in the treatment of T2DM is their potential to increase glucagon levels. As discussed previously, although the ability of EPAC2 to increase glucagon expression and production is controversial, several studies show that this protein increases Gcg mRNA levels in pancreatic islets. Hyperglucagonemia is a key problem usually seen in diabetic patients, and at least partially results from the inability of α flt3 to respond appropriately to hyperglycemia [73]. Hence, therapies that elevate glucagon levels are obviously undesirable in the treatment of diabetes. However, this potential side-effect of EPAC2 activators might be mitigated in two ways: increased insulin secretion by these drugs, because insulin inhibits glucagon secretion, and the addition of EPAC1 inhibitors. We speculate the latter class of molecules will combat hyperglucagonemia because it restores leptin sensitivity, which decreases glucagon levels [67].
Concluding remarks In summary, the roles of EPAC1 and EPAC2 in energy balance are complex. Despite recent major advances, our understanding remains limited and controversy persists in particular cases (Box 5). The generation of additional tissue-specific and conditional EPAC-knockout animal models will help to define further the physiological functions of EPAC. At the molecular and cellular levels, the dissection of EPAC signalosomes within the context of compartmentalized cAMP signaling will lead to further elucidation of EPAC-specific signaling pathways. In addition, it is necessary to expand EPAC pharmacological toolkits by developing novel isoform-specific small-molecule modulators, and also viable in vivo pharmacological probes. At present no isoform-specific EPAC agonists or EPAC1-specific antagonists are available. These pharmacological toolkits will be invaluable for interrogating the physiological functions of EPAC isoforms and for developing potential mechanism-based therapeutics targeting diseases where EPAC proteins are implicated.
Acknowledgments
Introduction Exchange proteins directly activated by cAMP (EPACs) were first identified as novel intracellular effector proteins of cyclic adenosine monophosphate (cAMP) by two independent groups in 1998 [1], [2]. Prior to the discovery of EPAC proteins, the major physiological effects of cAMP in mammalian cells are believed to be transduced by the classic protein kinase A/cAMP-dependent protein kinase (PKA/cAPK), and cyclic nucleotide-activated ion channels (CNG and HCN) in certain tissues [3], [4], [5], [6]. Between two ubiquitously expressed intracellular cAMP receptor families, EPAC proteins, unlike PKA, have no kinase activity but act as guanine nucleotide exchange factors to catalyze the exchange of GDP with GTP for the down-stream small GTPases, Rap1 and Rap2, in response to intracellular cAMP [1], [2]. Two structurally homologous but functionally nonredundant isoforms of mammalian EPAC proteins have been identified, EPAC1 and EPAC2. EPAC1 is more ubiquitously expressed, whereas the expression of EPAC2 is relatively restricted, mainly found in brain, pancreatic islets and adrenal gland [2]. From nearly two decades of research on EPAC, accumulating studies, including those with the aid of small-molecule EPAC modulators [7], [8] such as various cAMP analogues (e.g. 007-AM [9]) and newly discovered EPAC-specific antagonists (e.g. ESI-09 [10], [11], [12], [13], [14]), have demonstrated that EPAC proteins play important roles in insulin secretion, energy homeostasis, cardiovascular response, pain sensing, osteoclast differentiation, neurotransmitter release, Treg-mediated immune suppression, integrin-mediated cell adhesion, cell migration and proliferation, cell exocytosis, and apoptosis as well as gene transcription and chromosomal integrity [15], [16], [17], [18], [19], and thus represent potential therapeutic targets for various human diseases such as cancer, bacterial and viral infections, chronic pain, diabetes, obesity, and heart failure.