Cyclic AMP sensor EPAC proteins and energy homeostasis

Abstract

The pleiotropic second-messenger cAMP plays a crucial role in mediating the effects of various hormones on metabolism. The major intracellular functions of cAMP are transduced by protein kinase A (PKA) and by exchange proteins directly activated by cAMP (EPACs). The latter act as guanine-nucleotide exchange factors for the RAS-like small G proteins Rap1 and Rap2. Although the role of PKA in regulating energy balance has been extensively studied, the impact of EPACs remains relatively enigmatic. This review summarizes recent genetic and pharmacological studies concerning EPAC involvement in glucose homeostasis and energy balance via the regulation of leptin and insulin signaling pathways. In addition, the development of small-molecule EPAC-specific modulators and their therapeutic potential for the treatment of diabetes and obesity are discussed.

Keywords: cAMP; energy balance; exchange protein directly activated by cAMP (EPAC); insulin secretion; leptin resistance.

Figure 1. Leptin and insulin signaling pathways in the hypothalamus

Leptin binding to its receptor (OB-Rb) induces receptor dimerization and JAK2 activation. Phosphorylation of the intracellular domain of OB-Rb by JAK2 leads to the recruitment and phosphorylation of STAT3. Phosphorylated STAT3 dimerizes and translocates to the nucleus where it activates target genes under the control of pomc promoter and suppresses argp promoter. Leptin can also control hypothalamic neuron functions by activating the PI3K/Akt pathway in a manner similar to insulin. EPAC1 may desensitizes leptin signaling by suppressing STAT3 activation as it has been shown that EPAC1 induces the expression of SOCS3, a STAT3 negative regulator, by recruiting CCAAT/enhancer-binding protein (C/EBP) transcription factors to the SOCS-3 promoter in endothelial cells.

Figure 2. GSIS potentiation by EPAC2

a) Glucose enters pancreatic β-cells by facilitated diffusion and undergoes glycolysis and oxidative phosphorylation, leading to an increase in the ATP/ADP ratio. b) GLP-1 binds to its GLP-1R, which activates adenylyl cyclase (AC), which converts ATP to cAMP. c) The increase in ATP levels results in the closure of K_atp, membrane depolarization, and influx of extracellular Ca²⁺ through VDCC. EPAC2 is activated by cAMP and directly interacts with K_atp to facilitate the channel’s closure. EPAC2, through Rap1, also activates PLCε, which hydrolyzes PIP₂ in the vicinity of K_atp, increasing the likelihood of channel closure. d) Through activation of Rap1, EPAC2 mediates the trafficking of a pool of insulin vesicles called “resting newcomers (RNC)”, to replenish the “readily releasable pool (RRP)” located at the plasma membrane e) Activation of PLCε/CaMKII and IP₃ release after PIP₂ hydrolysis, facilitates CICR as the former enhances RyRs’ activity and the latter IP₃R’s. f) EPAC2 is involved directly in the fusion of insulin granules through formation of an EPAC2/Piccolo/Rim2/Rab3A complex and facilitation of SNARE complex assembly.

Figure 3. Therapeutic potential of EPAC small molecule modulators

EPAC1 inhibitors can potentially enhance hypothalamic leptin sensitivity, leading to an increase in satiety and energy expenditure, and augmentation of central and peripheral (liver) effects of insulin. EPAC2 activators can increase insulin secretion from pancreatic β-cells.

Figure I, Box 1

Intracellular cAMP sensors and signaling pathways. (a) Generation of second messenger cAMP in response to the activation of the G-protein coupled receptor cascade at the cell membrane and subsequent activation of intracellular cAMP receptors PKA and EPAC. (b) Domain architecture of EPAC and PKA.

Figure I, Box 2

Small molecule EPAC selective modulators. (a) EPAC selective cAMP analog 007 and its membrane permeable pro-drug 007-AM. (b) EPAC specific antagonists.