Integration of Rap1 and Calcium Signaling

Ca(2+) is a universal intracellular signal. The modulation of cytoplasmic Ca(2+) concentration regulates a plethora of cellular processes, such as: synaptic plasticity, neuronal survival, chemotaxis of immune cells, platelet aggregation, vasodilation, and cardiac excitation–contraction coupling. Rap1 GTPases are ubiquitously expressed binary switches that alternate between active and inactive states and are regulated by diverse families of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Active Rap1 couples extracellular stimulation with intracellular signaling through secondary messengers—cyclic adenosine monophosphate (cAMP), Ca(2+), and diacylglycerol (DAG). Much evidence indicates that Rap1 signaling intersects with Ca(2+) signaling pathways to control the important cellular functions of platelet activation or neuronal plasticity. Rap1 acts as an effector of Ca(2+) signaling when activated by mechanisms involving Ca(2+) and DAG-activated (CalDAG-) GEFs. Conversely, activated by other GEFs, such as cAMP-dependent GEF Epac, Rap1 controls cytoplasmic Ca(2+) levels. It does so by regulating the activity of Ca(2+) signaling proteins such as sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA). In this review, we focus on the physiological significance of the links between Rap1 and Ca(2+) signaling and emphasize the molecular interactions that may offer new targets for the therapy of Alzheimer’s disease, hypertension, and atherosclerosis, among other diseases.