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J Cell Biol. 2019 May 15. pii: jcb.201810118. doi: 10.1083/jcb.201810118. [Epub ahead of print]

Rab46 integrates Ca2+ and histamine signaling to regulate selective cargo release from Weibel-Palade bodies.

Author information

1
Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.
2
Faculty of Biological Sciences, University of Leeds, Leeds, UK.
3
Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK l.mckeown@leeds.ac.uk.
#
Contributed equally

Abstract

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.

PMID:
31092558
DOI:
10.1083/jcb.201810118

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