期刊
JOURNAL OF CELL BIOLOGY
卷 218, 期 7, 页码 2232-2246出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201810118
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资金
- Medical Research Council [MR/N000285/1]
- British Heart Foundation [FS/14/22/30734, FS/17/43/33003]
- Junta para la Ampliacion de Estudios predoctoral program from Consejo Superior de Investigaciones Cientificas
- MRC [MR/N000285/1] Funding Source: UKRI
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 H-1 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.
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