dictyNews
Electronic Edition
Volume 41, number 16
July 31, 2015

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Abstracts
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Dictyostelium Nramp1, structurally and functionally close to 
mammalian DMT1 transporter, mediates phagosomal iron efflux.

Simona Buracco1, Barbara Peracino1, Raffaella Cinquetti#, 
Elena Signoretto*, Alessandra Vollero#, Francesca Imperiali#, 
Michela Castagna*, Elena Bossi# and Salvatore Bozzaro1

1 Department of Clinical and Biological Sciences, University of 
Torino, AOU S. Luigi, 10043 Orbassano, Italy, 
#Department of Biotechnology and Life Sciences, University of 
Insubria, Via J. H. Dunant 3,  21100 Varese (Italy) and 
*Department of Pharmacological and Biomolecular Sciences, Universita 
degli Studi di Milano, Via Trentacoste 2, 20133 Milano (Italy)


J. Cell Sci., in press

The Nramp (Slc11) protein family is widespread in bacteria and 
eucaryotes, and mediates transport of divalent metals across cellular 
membranes. The social amoeba Dictyostelium discoideum harbours two 
Nramp proteins. Nramp1, like its mammalian ortholog, is recruited to 
phagosomal and macropinosomal membranes, and confers resistance to 
pathogenic bacteria. Nramp2 is located exclusively in the contractile 
vacuole membrane and controls, synergistically with Nramp1, iron 
homeostasis. It has long been debated whether mammalian Nramp1 
mediates iron import or export from phagosomes. By selectively loading 
the iron-chelating fluorochrome calcein in macropinosomes, we show that 
Dictyostelium Nramp1 mediates iron efflux from macropinosomes in vivo. 
To gain insight in ion selectivity and transport mechanism, the 
proteins were expressed in Xenopus oocytes. Using a novel assay with 
calcein, electrophysiological and radiochemical assays, we show that 
Nramp1, similarly to rat DMT1, transports iron(II) and manganese, 
not iron(III) or copper. Metal ion transport is electrogenic and 
proton-dependent. By contrast, Nramp2 transports only iron(II) in a 
non-electrogenic and proton-independent way. These differences reflect 
evolutionary divergence of the prototypical Nramp2 protein sequence 
compared to the archetypical Nramp1 and DMT1 proteins.


Submitted by Salvo Bozzaro [[log in to unmask]] 
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Matthew C. Walker and Robin S.B. Williams

New experimental therapies for status epilepticus in preclinical 
development


Epilepsy Behav, in press
This article is part of a Special Issue entitled "Status Epilepticus" 

Starting with the established antiepileptic drug, valproic acid, we 
have taken a novel approach to develop new antiseizure drugs that 
may be effective in status epilepticus. We first identified that 
valproic acid has a potent effect on a biochemical pathway, the 
phosphoinositide pathway, in Dictyostelium discoideum, and we 
demonstrated that this may relate to its mechanism of action against 
seizures in mammalian systems. Through screening in this pathway, we 
have identified a large array of fatty acids and fatty acid 
derivatives with antiseizure potential. These were then evaluated in 
an in vitro mammalian system. One compound that we identified through 
this process is a major constituent of the ketogenic diet, strongly 
arguing that it may be the fatty acids that are mediating the 
antiseizure effect of this diet. We further tested two of the more 
potent compounds in an in vivo model of status epilepticus and 
demonstrated that they were more effective than valproic acid in 
treating the status epilepticus. 


Submitted by Robin williams[[log in to unmask]] 
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[End dictyNews, volume 41, number 16]