| ironjustice@aol.com 2005-07-13, 11:11 pm |
| Am J Physiol Cell Physiol 288: C1117-C1124, 2005. First published
December 21, 2004; doi:10.1152/ajpcell.00444.2004
0363-6143/05 $8.00
CELLULAR METABOLISM
Iron alters glutamate secretion by regulating cytosolic aconitase
activity
M. Christine McGahan, Jill Harned, Marilyn Mukunnemkeril, Malgorzata
Goralska, Lloyd Fleisher, and Jenny B. Ferrell
Department of Molecular Biomedical Sciences, North Carolina State
University, Raleigh, North Carolina
Submitted 9 September 2004 ; accepted in final form 17 December 2004
Glutamate has many important physiological functions, including its
role as a neurotransmitter in the retina and the central nervous
system. We have made the novel observations that retinal pigment
epithelial cells underlying and intimately interacting with the retina
secrete glutamate and that this secretion is significantly affected by
iron. In addition, iron increased secretion of glutamate in cultured
lens and neuronal cells, indicating that this may be a common mechanism
for the regulation of glutamate production in many cell types. The
activity of the iron-dependent enzyme cytosolic aconitase (c-aconitase)
is increased by iron. The conversion of citrate to isocitrate by
c-aconitase is the first step in a three-step process leading to
glutamate formation. In the present study, iron increased c-aconitase
activity, and this increase was associated with an increase in
glutamate secretion. Inhibition of c-aconitase by oxalomalate decreased
glutamate secretion and completely inhibited the iron-induced increase
in glutamate secretion. Derangements in both glutamate secretion and
iron metabolism have been noted in neurological diseases and retinal
degeneration. Our results are the first to provide a functional link
between these two physiologically important substances by demonstrating
a significant role for iron in the regulation of glutamate production
and secretion in mammalian cells resulting from iron regulation of
aconitase activity. Glutamatergic systems are found in many nonneuronal
tissues. We provide the first evidence that, in addition to secreting
glutamate, retinal pigment epithelial cells express the vesicular
glutamate transporter VGLUT1 and that regulated vesicular release of
glutamate from these cells can be inhibited by riluzole.
retinal pigment epithelial cells; lens epithelial cells
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Address for reprint requests and other correspondence: M. C. McGahan,
Dept. of Molecular Biomedical Sciences, North Carolina State Univ.,
4700 Hillsborough St., Raleigh, NC 27606 (E-mail:
chris_mcgahan@ncsu.edu)
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