CaSR links endocytic and secretory pathways via MADD, a Rab11A effector that activates Rab27B.

Calcium sensing receptor (CaSR), a class C GPCR, regulates essential secretory pathways, involving communication between endocytic and secretory Rab GTPases, via still to be fully defined molecular mechanisms. To address how communication between endocytic and secretory vesicles occurs, we hypothesized that CaSR activates endocytic Rab11A-dependent effector pathways acting upstream of Rab27B-regulated secretion. We found that Rab11A is critical to promote Rab27B-dependent secretion of chemotactic and inflammatory factors, including IL-8, CCL2/MCP-1, and IL1-β, in response to CaSR stimulation. It also attenuates secretion of IL-6. The process is mediated by endosomal PI3-kinases, Vps34 and PI3KC2α, which promote Rab27B activation. Rab11A interacts with and activates MADD, a guanine exchange factor for Rab3, and Rab27A/B. Mechanistically, CaSR drives Rab11A-dependent coupling of recycling endosomes to secretory-vesicles via endosomal PI3K-mediated activation of a MADD/Rab27B pathway.