Mechanism of action of the non-steroidal anti-inflammatory drug flufenamate on [Ca2+]i and Ca(2+)-activated currents in neurons.
We have shown previously that the non-steroidal anti-inflammatory drug flufenamate (FFA) causes a maintained increase in [Ca2+]i and transient increases in a Ca(2+)-activated nonselective cation current (ICAN) and a Ca(2+)-activated slow, outward Cl- current (lo-slow) in molluscan neurons [Shaw T., Lee R.J., Partridge L.D. Action of diphenylamine carboxylate derivatives, a family of non-steroidal anti-inflammatory drugs, on [Ca2+]i and Ca(2+)-activated channels in neurons. Neurosci Lett 1995; 190:121-124]. Here we demonstrate that pretreatment of neurons with 10 microM thapsigargin eliminates the FFA-induced increase in [Ca2+]i and substantially reduces both ICAN and Io-slow supporting the hypothesis that the FFA-induced increase in [Ca2+]i results primarily from Ca2+ release from a thapsigargin-sensitive intracellular store. The [Ca2+]i response appears to be sustained, not by influx of extracellular Ca2+, but by inhibitory effects of FFA on Ca2+ removal from the cytosol. Inhibition of Ca2+ efflux may be an important component of the FFA-induced activation of both ICAN and Io-slow, as Ca2+ release by thapsigargin alone is not sufficient to activate either current. Our data also demonstrate that the effects of FFA on [Ca2+]i, ICAN and Io-slow are reversible and suggest that protein phosphorylation as well as an increase in [Ca2+]i are involved in the FFA-induced activation of Io-slow. Effects on neuronal Ca2+ handling as well as activation of ICAN or Io-slow may partially explain the analgesic effects of FFA.
Lee
R J
RJ
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, USA.
Shaw
T
T
Sandquist
M
M
Partridge
L D
LD
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D005439:Flufenamic Acid / Q000494:pharmacology*; D017136:Ion Transport; D009474:Neurons / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005439:Flufenamic Acid; D002118:Calcium