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Vol. 298, Issue 3, 1033-1041, September 2001
Department of Cell Biology, Institute of Cellular Signaling,
University of Nijmegen, The Netherlands (E.G.A.H., A.D.G.d.R.,
P.H.J.P., D.L.Y., E.J.J.v.Z., A.P.R.T.); Division of Toxicology,
Department of Food Technology and Nutritional Sciences, Wageningen
Agricultural University and Research Center, The Netherlands (L.H.d.H.,
A.B.)
The effect of fenamates on gap junctional intercellular communication
was investigated in monolayers of normal rat kidney (NRK) fibroblasts
and of SKHep1 cells overexpressing the gap junction protein connexin43
(Cx43). Using two different methods to study gap junctional
intercellular communication, single electrode voltage-clamp step
response measurements and dye microinjection, we show that fenamates
are reversible blockers of Cx43-mediated intercellular communication.
After adding fenamates to a confluent monolayer of electrically coupled
NRK fibroblasts, the voltage step-induced capacitive current transient
changed from a transient characteristic for charging multiple coupled
cell capacitances to one characteristic for a single cell in isolation.
The capacitance of completely uncoupled cells was 19.7 ± 1.0 pF
(mean ± S.E.M.; n = 11). Junctional conductance between the patched cell and the surrounding cells in the
monolayer changed from >140.7 ± 9.6 nS (mean ± S.E.M.; n = 14) to <1.4 ± 0.4 nS (mean ± S.E.M.; n = 11) after uncoupling. Electrical
coupling could be restored to >51.8 ± 4.2 nS (mean ± S.E.M.; n = 11) by washout of the fenamates.
Voltage-clamp step response measurements showed that the potency of
fenamates in inhibiting electrical coupling decreases in the order
meclofenamic acid > niflumic acid > flufenamic acid. The
half-maximal concentration determined by dye-coupling experiments was
25 and 40 µM for meclofenamic acid and flufenamic acid, respectively.
Inhibition of gap junctional communication by fenamates did not involve
changes in intracellular calcium or pH, and was unrelated to protein
kinase C activity or an inhibition of cyclooxygenase activity.
Voltage-clamp step response measurements in confluent monolayers of
SKHep1 cells that had been stably transfected with Cx43 revealed that
fenamates are potent blockers of Cx43-mediated intercellular
communication. In conclusion, fenamates represent a novel class of
reversible gap junction blockers that can be used to study the role of
Cx43-mediated gap junctional intercellular communication in biological processes.
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