RGD Reference Report - Coordinate regulation of catecholamine uptake by rab3 and phosphoinositide 3-kinase. - Rat Genome Database

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Coordinate regulation of catecholamine uptake by rab3 and phosphoinositide 3-kinase.

Authors: Francis, SC  Sunshine, C  Kirk, KL 
Citation: Francis SC, etal., J Biol Chem 2002 Mar 8;277(10):7816-23.
RGD ID: 729623
Pubmed: PMID:11748228   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M109743200   (Journal Full-text)

Previously we observed that rab3 GTPases modulate both the secretion of catecholamines from PC12 neuroendocrine cells and the steady-state accumulation of exogenous norepinephrine (NE) into these cells (Weber, E., Jilling, T., and Kirk, K. L. (1996) J. Biol. Chem. 271, 6963-6971). Here we addressed the mechanisms by which these monomeric GTPases stimulate NE uptake by PC12 cells including their effects on uptake kinetics, their sites of action (secretory granule membrane versus plasma membrane), and the involvement of rab3-interacting proteins in this process. We observed that rab3B stimulated the rate and maximal accumulation of radiolabeled NE into large dense core vesicles within intact PC12 cells. rab3A and rab3B also increased NE uptake into large dense core vesicles in digitonin-permeabilized PC12 cells, which indicates that these GTPases stimulate catecholamine uptake at the level of the secretory granule membrane. In an attempt to identify rab3B targets that may mediate this effect on NE uptake, we found that rab3B interacts directly with phosphoinositide 3-kinase (PI3K) in a GTP-dependent fashion and that PI3K activity was elevated in PC12 cells overexpressing rab3B. Furthermore, two structurally distinct inhibitors of PI3K (wortmannin and LY294002) inhibited NE uptake in intact as well as digitonin-permeabilized PC12 cells, but had no effect on calcium-evoked NE secretion. Our results indicate that rab3 and PI3K positively and coordinately regulate NE uptake in PC12 neuroendocrine cells at least in part by stimulating the secretory vesicle uptake step.

Objects referenced in this article
Gene Pik3r1 phosphoinositide-3-kinase regulatory subunit 1 Rattus norvegicus
Gene Rab3a RAB3A, member RAS oncogene family Rattus norvegicus

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