 Since the landmark discovery of the prototypic second messenger cAMP in 1957, three families of eukaryotic cAMP receptors have been identified to mediate the intracellular functions of cAMP.While protein kinase A (PKA) or cAMP-dependent protein kinase and cyclic nucleotide regulated ion channel (CNG and HCN) were initially unveiled in 1968 and 1985 respectively; EPAC genes were discovered in 1998 independently by two research groups.Kawasaki et al.