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Vol. 286, Issue 1, 243-255, July 1998
-Aminobutyric Acid Receptor
Function: Role of Protein Tyrosine Phosphorylation and
Calcineurin1
Department of Pharmacology, University of North Texas Health
Science Center at Fort Worth, Fort Worth, Texas
In the present study, rundown of 
-aminobutyric acid (GABA)-activated
Cl
channels was studied in recombinant GABAA
receptors stably expressed in human embryonic kidney cells (HEK 293),
with conventional whole-cell and amphotericin B-perforated patch
recording. When [ATP]i was lowered to 1 mM and resting
[Ca++]i was buffered to a relatively high
level, the response of 
3 
2 2 GABAA receptors to
relatively low [GABA] (up to 50 µM) did not show rundown in the
whole-cell configuration. However, high [GABA] (greater than 200 µM) induced significant rundown, which was observed by decreases in
both the maximum GABA-induced current and GABA EC50.
Rundown was prevented completely with a solution containing 4 mM
Mg++-ATP and low resting [Ca++]i,
or during perforated patch recording. The magnitude of rundown was
comparable in 1 2 2 and 2 2 receptors. Neither
stimulation nor inhibition of protein kinase A or protein kinase C had
a significant effect on rundown. However, sodium metavanadate, an
inhibitor of protein tyrosine phosphatase, significantly reduced
rundown. In addition, inhibition of protein tyrosine kinase activity by either genistein or lavendustin A induced rundown of the GABA response.
Inhibition of the Ca++/calmodulin-dependent phosphatase
calcineurin with fenvalerate also prevented rundown of the response to
GABA. Our results demonstrate that rundown of GABAA
receptor function is concentration-dependent, due to depletion of ATP
and/or unbuffered [Ca++]i, and does not
depend on the presence or subtype of the alpha subunit.
We propose that protein phosphorylation at a tyrosine kinase-dependent
site, and a distinct unidentified site, which is dephosphorylated by
calcineurin, maintains the function of GABAA receptors.
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