DIFFERENTIAL MODULATION OF ALPHA-3-BETA-2 AND ALPHA-3-BETA-4 NEURONAL NICOTINIC RECEPTORS EXPRESSED IN XENOPUS OOCYTES BY FLUFENAMIC ACID AND NIFLUMIC ACID

Effects of flufenamic acid (FFA) and niflumic acid (NFA), which are often used to block Ca2+-activated Cl- current, have been investigated in voltage-clamped Xenopus oocytes expressing alpha 3 beta 2 and alpha 3 beta 4 nicotinic ACh receptors (nAChRs). NFA and FFA inhibit alpha 3 beta 2 nAChR-mediated inward currents and potentiate alpha 3 beta 4 nAChR-mediated inward currents in normal, Cl--free and Ca2+-free solutions to a similar extent. The concentration-dependence of the inhibition of alpha 3 beta 2 nAChR-mediated ion current yields IC50 values of 90 mu M for FFA and of 260 mu M for NFA. The potentiation of alpha 3 beta 4 nAChR-mediated ion current by NFA yields an EC(50) value of 30 mu M, whereas the effect of FFA does not saturate for concentrations of up to 1 mM. At 100 mu M, FFA reduces the maximum of the concentration-effect curve of ACh for alpha 3 beta 2 nAChRs, but leaves the EC(50) of ACh unaffected. The same concentration of FFA potentiates alpha 3 beta 4 nAChR-mediated ion currents for all ACh concentrations and causes a small shift of the concentration-effect curve of ACh to lower agonist concentrations. The potentiation, like the inhibition, is most likely due to a noncompetitive effect of FFA. Increasing ACh-induced inward current either by raising the agonist concentration from 10 mu M to 200 mu M or by coapplication of 10 mu M ACh and 200 mu M FFA causes a similar enhancement of block of the alpha 3 beta 4 nAChR-mediated ion current by Mg2+. This suggests that the effects of FFA and of an increased agonist concentration result in a similar functional modification of the alpha 3 beta 4 nAChR-operated ion channel. It is concluded that alpha 3 beta 4 and alpha 3 beta 2 nAChRs are oppositely modulated by FFA and NFA through a direct beta-subunit-dependent effect.