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Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York
We determined the effect of flufenamic acid (FFA) and related derivatives
on gap junction channel currents, applying the dual whole-cell patch-clamp
technique to pairs of N2A neuroblastoma cells transfected with various
connexins. FFA reduced gap junction channel currents in a reversible and
concentration-dependent manner. Half-maximal concentrations for FFA-induced
reduction of junctional conductance in cell pairs coupled by different
connexins were similar (20 to 60 µM), indicating that FFA does not greatly
discriminate between connexin subtypes. Hill coefficients for blockade were
approximately 3, indicating a high degree of cooperativity. Analogs of FFA
also reduced junctional conductance with similar potencies, whereas other
unrelated chloride channel blockers had no effect. Inhibition of gap junction
channels by FFA (pKa 
3.8) was increased at low
external pH, suggesting that the uncharged form of the drug is important for
blockade. The effect of FFA did not seem to be mediated by direct binding of
the drug to the pore of the gap junction channel. Internal application of high
concentrations of FFA by addition to patch pipettes did not cause inhibition
of channel currents. The magnitude of inhibition was neither voltage-dependent
nor influenced by the nature of permeant ion. Single-channel recordings
indicated that FFA reduced the channel-open probability without modifying the
current amplitude and induced slow transitions between open and closed states.
We propose that FFA inhibits gap junctions by inducing a conformational change
in the protein upon binding to a site that is presumably located within the
membrane.
Address correspondence to: Dr. Miduturu Srinivas, Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461. E-mail: msriniva{at}aecom.yu.edu
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