Epac and PKA: a tale of two intracellular cAMP receptors

Abstract

cAMP-mediated signaling pathways regulate a multitude of important biological processes under both physiological and pathological conditions, including diabetes, heart failure and cancer. In eukaryotic cells, the effects of cAMP are mediated by two ubiquitously expressed intracellular cAMP receptors, the classic protein kinase A (PKA)/cAMP-dependent protein kinase and the recently discovered exchange protein directly activated by camp (Epac)/cAMP-regulated guanine nucleotide exchange factors. Like PKA, Epac contains an evolutionally conserved cAMP binding domain that acts as a molecular switch for sensing intracellular second messenger cAMP levels to control diverse biological functions. The existence of two families of cAMP effectors provides a mechanism for a more precise and integrated control of the cAMP signaling pathways in a spatial and temporal manner. Depending upon the specific cellular environments as well as their relative abundance, distribution and localization, Epac and PKA may act independently, converge synergistically or oppose each other in regulating a specific cellular function.

Fig. 1. Domain structure of Epac

Linear representation of Epac, PKA, and CRP showing the conserved cAMP binding domain (CBD), Dishevelled/Egl-10/pleckstrin (DEP) domain, RAS exchange motif (REM) domain, RAS association (RA) domain, and CDC25-homology domain (CDC25HD).

Fig. 2. Mechanism of Epac activation, a model

Schematic representation of cAMP-induced Epac activation with the DEP, CBD, REM, RA, and CDC25HD domains colored in pink, green, blue, red and cyan, respectively. In the cAMP-free, inactive Epac state, the regulatory region is anchored by the switchboard to keep the CBD in close proximity of the catalytic core to prevent the binding of Rap. Upon binding of cAMP, the β strands S1 and S2 break away from the switchboard, fold back towards the β barrel and interact directly with cAMP to form the base of the cAMP-binding pocket. This localized hinge motion reorients the CDC25HD homology domain relative to CBD, and ultimately leads to an open Epac conformation and the exposure of the catalytic core of Epac for the access of Rap GTPase.