FIG. 8.

Diagram summarizing β₁-adrenergic signaling via PKA and Epac-Rap1. The presence of a β₁-ADR agonist increases the production of cAMP via AC. cAMP acts simultaneously via both PKA and Epac pathways to influence the function of intracellular targets that control Ca²⁺ signaling, force production, electrical connectivity, and cell survival. Some effects of Epac are mediated via its role as a guanine nucleotide exchange factor for the small GTPase Rap1, which facilitates the release of guanosine diphosphate, thereby increasing the level of active Rap1 GTP. The GTPase-activating protein, RAP-GAP, opposes this effect by facilitating GTP hydrolysis. Geranylgeranylation of active Rap1 via GGT-1 is required for interaction with downstream membrane targets. Our data suggest that Rap1GTP is a negative regulator of ROS production by the mitochondria. When Epac2 or GGT-1 is inhibited, the increase in ROS is associated with activation of CaMKII and the development of EAD arrhythmias due to increased INa_Late and AP prolongation. Arrhythmias can be prevented by inhibition of CaMKII with KN93, preincubation with the mitochondria-targeted antioxidant mitoTEMPO, or inhibition of INa_Late with ranolazine. AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; ROS, reactive oxygen species. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars