Integration of Rap1 and Calcium Signaling.

Ramoji Kosuru,Magdalena Chrzanowska

doi:10.3390/ijms21051616

Abstract

Ca2+ is a universal intracellular signal. The modulation of cytoplasmic Ca2+ 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), Ca2+, and diacylglycerol (DAG). Much evidence indicates that Rap1 signaling intersects with Ca2+ signaling pathways to control the important cellular functions of platelet activation or neuronal plasticity. Rap1 acts as an effector of Ca2+ signaling when activated by mechanisms involving Ca2+ and DAG-activated (CalDAG-) GEFs. Conversely, activated by other GEFs, such as cAMP-dependent GEF Epac, Rap1 controls cytoplasmic Ca2+ levels. It does so by regulating the activity of Ca2+ signaling proteins such as sarcoendoplasmic reticulum Ca2+-ATPase (SERCA). In this review, we focus on the physiological significance of the links between Rap1 and Ca2+ signaling and emphasize the molecular interactions that may offer new targets for the therapy of Alzheimer’s disease, hypertension, and atherosclerosis, among other diseases.

Highlights

Rap1, a 21 kDa monomeric G-protein, was discovered in 1989 by Noda and his coworkers in a screen for proteins able to suppress the oncogenic effect of K-Ras [1]
Interaction of PDE4D and Epac1 is critical for the integration into the VE-cadherin-based signaling complex and the coordination of cyclic adenosine monophosphate (cAMP)-mediated vascular endothelial cell adhesion and permeability [22]
Increased cAMP production leads to the phosphorylation of Rap1b and its subsequent dissociation from sarcoendoplasmic reticulum Ca2+-ATPases (SERCA) 3b protein results in the stimulation of its activity to enhance the filling state of SERCA-associated Ca2+ pool to induce platelet inhibition [95] (Figure 2)

Summary

CalDAG-GEFs

The discovery of a Ca2+-binding GEF, CalDAG-GEFII, encoded by RASGRP1 gene, with an activity towards Ras, introduced an intriguing possibility of a cross-talk between the Ca2+ and Rap signaling pathways [44] This possibility materialized when a second family member, CalDAG-GEFI (RASGRP2) was identified as a novel brain transcript, and was shown to activate Rap proteins [45,46]. The dopamine D1 receptor-induced, PKA-mediated Ca2+ release activates the Rap1/B-Raf/ERK pathway to regulate cAMP-response element binding protein (CREB)-phosphorylation and gene expression [77] (Figure 1). This mechanism of Rap activation appears to be primed by PKA-induced Ca2+ release, but is not further induced by direct or indirect PKA- or protein kinase C-dependent phosphorylation [77].

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Vascular Smooth Muscle Cells

10. Endothelium

11. Conclusions and Future Perspectives