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J Neurophysiol (January 1, 2003). 10.1152/jn.00229.2002
Submitted on Submitted 29 March 2002; accepted in final form 17 September 2002
Departments of 1Neurological Surgery, and 2Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53792; and 3Department of Cellular and Molecular Physiology, Yale University, School of Medicine, New Haven, Connecticut 06520
Schomberg, Stacey L.,
James Bauer,
Douglas B. Kintner,
Gui Su,
Andreas Flemmer,
Biff Forbush, and
Dandan Sun.
Cross Talk Between the GABAA Receptor and the Na-K-Cl
Cotransporter Is Mediated by Intracellular Cl. J. Neurophysiol. 89: 159-167, 2003. It has been suggested that the
GABAA receptor-mediated depolarization in
immature neurons depends on a high intracellular Cl
concentration maintained by Na-K-Cl
cotransporter isoform1 (NKCC1). We previously found that activation of
the GABAA receptor led to stimulation of NKCC1.
This stimulation could be a result of GABAA
receptor-mediated Cl efflux. However, a loss of
intracellular Cl is associated with cell
shrinkage, membrane depolarization, as well as a rise of intracellular
Ca2+ concentration
([Ca2+]i). To determine
which cellular mechanism is underlying NKCC1 stimulation, we
investigated changes of intracellular Cl
content, [Ca2+]i, cell
volume, and NKCC1 activity following GABAA
receptor activation. The basal levels of intracellular
36Cl were 0.70 ± 0.04 µmol/mg protein.
The intracellular 36Cl content decreased to
0.53 ± 0.03 µmol/mg protein in response to 30 µM muscimol
(P < 0.05). The loss of intracellular
36Cl was blocked by 10 µM bicuculline. Muscimol
triggered a rise in [Ca2+]i,
but did not cause cell shrinkage. In contrast, 10-50 mM
[Cl]o or hypertonic
HEPES-MEM resulted in reversible cell shrinkage (P < 0.05). Moreover, the GABA-mediated stimulation of NKCC1 activity was
not abolished either by removal of extracellular
Ca2+ or BAPTA-AM. An increase in phosphorylation
of NKCC1 was detected under both 10 mM
[Cl]o and muscimol
conditions. These results suggest that a GABA-mediated loss of
intracellular Cl, but not a subsequent rise in
[Ca2+]i or shrinkage,
leads to stimulation of NKCC1. This stimulation may be an important
positive feedback mechanism to maintain intracellular Cl level and GABA function in immature neurons.
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