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J. Biol. Chem., Vol. 278, Issue 3, 1966-1974, January 17, 2003
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From the L-Glutamate is believed to
function as an intercellular transmitter in the islets of Langerhans.
However, critical issues, i.e. where, when and how
L-glutamate appears, and what happens upon stimulation of
glutamate receptors in the islets, remain unresolved. Vesicular
glutamate transporter 2 (VGLUT2), an isoform of the vesicular glutamate
transporter essential for neuronal storage of L-glutamate,
is expressed in
Secretory Granule-mediated Co-secretion of
L-Glutamate and Glucagon Triggers Glutamatergic Signal
Transmission in Islets of Langerhans*
§,¶,,,,
,, and§§
Department of Biochemistry, Faculty of
Pharmaceutical Sciences, Okayama University, Okayama 700-8530, the
** Department of Cell Biology, Institute for Molecular and
Cellular Regulation, Gunma University, Maebashi 371-8512, and the
Department of Physiology, Kansai Medical
University, Moriguchi, Osaka 570-8506, Japan
cells (Hayashi, M., Otsuka, M., Morimoto, R.,
Hirota, S., Yatsushiro, S., Takeda, J., Yamamoto, A., and Moriyama, Y. (2001) J. Biol. Chem. 276, 43400-43406). Here we show
that VGLUT2 is specifically localized in glucagon-containing secretory
granules but not in synaptic-like microvesicles in TC6 cells,
clonal cells, and islet cells. VGLUT1, another VGLUT isoform,
is also expressed and localized in secretory granules in cells. Low
glucose conditions triggered co-secretion of stoichiometric amounts of
L-glutamate and glucagon from TC6 cells and isolated
islets, which is dependent on temperature and Ca2+ and
inhibited by phentolamine. Similar co-secretion of
L-glutamate and glucagon from islets was observed upon
stimulation of 
-adrenergic receptors with isoproterenol. Under low
glucose conditions, stimulation of glutamate receptors facilitates
secretion of 
-aminobutyric acid from MIN6 m9, clonal cells, and isolated islets. These results indicate that co-secretion of
L-glutamate and glucagon from cells under low glucose
conditions triggers GABA secretion from cells and defines the mode
of action of L-glutamate as a regulatory molecule for the
endocrine function. To our knowledge, this is the first example of
secretory granule-mediated glutamatergic signal transmission.
*
This study was supported by a grant-in-aid for Scientific
Research from the Ministry of Education, Science, Sports, and Culture of Japan, Core Research for Evolutional Science, the Yamanouchi Foundation for Research on Metabolic Disorders, the Takeda Science Foundation, and the Umami Research Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by a Research Fellowship from the Japan Society for
the Promotion of Science for Young Scientists.
§§
To whom correspondence should be addressed. Tel.:
81-86-251-7933; Fax: 81-86-251-7933; Email:
moriyama@pheasant.pharm.okayama-u.ac.jp.
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