Differential Modulation of c~3p2 and a3p4 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 Clcurrent, have been investigated in voltage-clamped Xenopus oocytes expressing 01392 and a364 nicotinic ACh receptors (nAChRs). NFA and FFA inhibit a362 nAChR-mediated inward currents and potentiate ~364 nAChR-mediated inward currents in normal, Cl--free and Ca*+-free solutions to a similar extent. The concentration-dependence of the inhibition of ~~362 nAChR-mediated ion current yields IC,, values of 90 PM for FFA and of 260 PM for NFA. The potentiation of a364 nAChR-mediated ion current by NFA yields an EC,, value of 30 PM, whereas the effect of FFA does not saturate for concentrations of up to 1 mu. At 100 PM, FFA reduces the maximum of the concentration-effect curve of ACh for ar362 nAChRs, but leaves the EC,, of ACh unaffected. The same concentration of FFA potentiates a394 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 PM to 200 PM or by coapplication of 10 JLM ACh and 200 PM FFA causes a similar enhancement of block of the or364 nAChR-mediated ion current by Mg*+. This suggests that the effects of FFA and of an increased agonist concentration result in a similar functional modification of the ~~364 nAChR-operated ion channel. It is concluded that a364 and ~~362 nAChRs are oppositely modulated by FFA and NFA through a direct p-subunit-dependent effect. [