The second messenger cAMP is known to augment glucose-induced insulin secretion. However, its downstream targets in pancreatic β-cells have not been unequivocally determined. Therefore, we designed cAMP analogues by a structure-guided approach that act as Epac2-selective agonists both in vitro and in vivo. These analogues activate Epac2 about two orders of magnitude more potently than cAMP. The high potency arises from increased affinity as well as increased maximal activation. Crystallographic studies demonstrate that this is due to unique interactions. At least one of the Epac2-specific agonists, Sp-8-BnT-cAMPS (S-220), enhances glucose-induced insulin secretion in human pancreatic cells. Selective targeting of Epac2 is thus proven possible and may be an option in diabetes treatment.
cAMP is a small molecule produced by cells that activates proteins involved in a wide range of biological processes, including olfaction, pacemaker activity, regulation of gene expression, insulin secretion, and many others. In the case of insulin secretion, cAMP seems to impinge on different stages of the signalling cascade to regulate secretory activity in pancreatic β-cells. Here we have developed a chemically modified version of cAMP that specifically only activates Epac2, one of the cAMP-responsive proteins in this cascade. Furthermore, our cAMP analogue activates Epac2 more potently than cAMP itself does. We have determined several crystal structures of Epac2 in complex with cAMP analogues to help us explain the molecular basis of the observed selectivity and the strong activation potential. In addition, we were able to show that the analogue is able to potentiate glucose-induced secretion of insulin from human pancreatic islets. The principal challenge during this study was identifying and understanding small differences in the cAMP-binding domains of cAMP-regulated proteins and matching these differences with suitable modifications of the cAMP molecule.
A newly developed analogue of cAMP that selectively activates Epac2 can potentiate glucose-induced insulin secretion from human pancreatic β-cells.