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1
* Department of Pharmacology and
Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA
1Correspondence: Department of Pharmacology, CB #7365 Mary Ellen Jones Bldg., University of North Carolina, Chapel Hill, NC 27599-7365, USA. E-mail: thurman{at}med.unc.edu
Recently, it was demonstrated that liver injury and TNF-
production
as a result of endotoxin (lipopolysaccharide, LPS) were attenuated by
feeding animals a diet enriched with glycine. This phenomenon was shown
to be a result of, at least in part, activation of a chloride channel
in Kupffer cells by glycine, which hyperpolarizes the cell membrane and
blunts increases in intracellular calcium concentrations
([Ca2+]i) similar to its action in the
neuron. It is well known that hepatotoxicity due to LPS has a
neutrophil-mediated component and that activation of neutrophils is
dependent on increases in [Ca2+]i. Therefore,
the purpose of this study was to determine if glycine affected
agonist-induced increases in [Ca2+]i in rat
neutrophils. The effect of glycine on increases in
[Ca2+]i elicited either by the
bacterial-derived peptide formyl-methionine-leucine–phenylalanine
(FMLP) or LPS was studied in individual neutrophils using Fura-2 and
fluorescence microscopy. Both FMLP and LPS caused dose-dependent
increases in [Ca2+]i, which were maximal at 1
µM FMLP and 100 µg/ml LPS, respectively. LPS increased
intracellular calcium in the presence and absence of extracellular
calcium. Glycine blunted increases in [Ca2+]i
in a dose-dependent manner with an IC50 of ~0.3 mM,
values only slightly higher than plasma levels. Glycine was unable to
prevent agonist-induced increases in [Ca2+]i
in chloride-free buffer. Moreover, strychnine (1 µM), an antagonist
of the glycine-gated chloride channel in the central nervous system,
reversed the effects of glycine (1 mM) on FMLP- or LPS-stimulated
increases in [Ca2+]i. To provide hard
evidence for a glycine-gated chloride channel in the neutrophil, the
effect of glycine on radioactive chloride uptake was determined.
Glycine caused a dose-dependent increase in chloride uptake into
neutrophils with an ED50 of ~0.4 mM, an effect also
prevented by 1 µM strychnine. Glycine also significantly reduced the
production of superoxide anion from FMLP-stimulated neutrophils. Taken
together, these data provide clear evidence that neutrophils contain a
glycine-gated chloride channel that can attenuate increases in
[Ca2+]i and diminish oxidant production by
this important leukocyte.—Wheeler, M., Stachlewitz, R. F.,
Yamashina, S., Ikejima, K., Morrow, A. L., and Thurman, R. G.
Glycine-gated chloride channels in neutrophils attenuate calcium influx
and superoxide production.
Key Words: glycine • strychnine • intracellular calcium • lipopolysaccharide • formyl-methionine-leucine-phenylalanine
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