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Fenamates: A Novel Class of Reversible Gap Junction Blockers
Open accessAbstract
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 microM 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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Nonsteroidal anti-inflammatory drugs in Alzheimer's disease
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Carcinoma–astrocyte gap junctions promote brain metastasis by cGAMP transfer
Chen, Q., Boire, A., Jin, X., Valiente, M., Er, E. E., Lopez-Soto, A., S. Jacob, L., Patwa, R., Shah, H., Xu, K., et al. (2016) · Nature · doi:10.1038/nature18268 · Cited by 969
Liu, X., Wang, Q., Haydar, T. F., & Bordey, A. (2005) · Nature Neuroscience · doi:10.1038/nn1522 · Cited by 444
The gap junction cellular internet: connexin hemichannels enter the signalling limelight
Evans, W. H., De Vuyst, E., & Leybaert, L. (2006) · Biochemical Journal · doi:10.1042/bj20060175 · Cited by 411
Nielsen, M. S., Nygaard Axelsen, L., Sorgen, P. L., Verma, V., Delmar, M., & Holstein‐Rathlou, N. (2012) · Comprehensive Physiology · doi:10.1002/cphy.c110051 · Cited by 386
Wang, X., Veruki, M. L., Bukoreshtliev, N. V., Hartveit, E., & Gerdes, H.-H. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006785107 · Cited by 337
Metadata
- Authors
- Harks, E. G. A., de Roos, A. D. G., Peters, P. H. J., de Haan, L. H., Brouwer, A., Ypey, D. L., van Zoelen, E. J. J., & Theuvenet, A. P. R.
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2001-09
- Volume
- 298
- Issue
- 3
- Pages
- 1033-1041
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2161774676
- Cited by
- 167
- References
- 1
- FWCI
- 2.28
- Type
- journal article
- Language
- en
- Open access
- green
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- Harks, E. G. A., de Roos, A. D. G., Peters, P. H. J., de Haan, L. H., Brouwer, A., Ypey, D. L., van Zoelen, E. J. J., & Theuvenet, A. P. R. (2001). Fenamates: A Novel Class of Reversible Gap Junction Blockers. The Journal of Pharmacology and Experimental Therapeutics. https://doi.org/10.1016/s0022-3565(24)29472-6
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