Endothelial cells selectively release cargo stored in Weibel-Palade bodies (WPBs) to regulate vascular function, but the underlying mechanisms are poorly understood. Here we show that histamine evokes the release of the proinflammatory ligand, P-selectin, while diverting WPBs carrying non-inflammatory cargo away from the plasma membrane to the microtubule organizing center. This differential trafficking is dependent on Rab46 (CRACR2A), a newly identified Ca2+-sensing GTPase, which localizes to a subset of P-selectin–negative WPBs. After acute stimulation of the H1 receptor, GTP-bound Rab46 evokes dynein-dependent retrograde transport of a subset of WPBs along microtubules. Upon continued histamine stimulation, Rab46 senses localized elevations of intracellular calcium and evokes dispersal of microtubule organizing center–clustered WPBs. These data demonstrate for the first time that a Rab GTPase, Rab46, integrates G protein and Ca2+ signals to couple on-demand histamine signals to selective WPB trafficking.
Colorectal cancer (CRC) is the third most frequent form of cancer worldwide. Recent evidence suggests that intracellular Ca remodeling may contribute to cancer hallmarks. In addition, aspirin and other NSAIDs might prevent CRC acting on remodeled Ca entry pathways. In this review, we will briefly describe 1) the players involved in intracellular Ca homeostasis with a particular emphasis on the mechanisms involved in SOCE activation and inactivation, 2) the evidence that aspirin metabolite salicylate and other NSAIDs inhibits tumor cell growth acting on SOCE, 3) evidences on the remodeling of intracellular Ca in cancer with a particular emphasis in SOCE, 4) the remodeling of SOCE and Ca store content in CRC and, finally, 5) the molecular basis of Ca remodeling in CRC. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.
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