Modulation of glutamate and glycine transporters by niflumic, flufenamic and mefenamic acids.
Three fenamates--niflumic, flufenamic and mefenamic acids--were tested for effects on substrate-induced currents of glutamate and glycine transporters (EAAT1, EAAT2, GLYT1b and GLYT2a) expressed in Xenopus laevis oocytes. All fenamates inhibited EAAT1 currents; 100 microM flufenamic acid produced the most inhibition, decreasing the I (max) by 53 +/- 4% (P < 0.001). EAAT2 currents were less sensitive, but 100 microM flufenamic acid inhibited the I (max) by 34 +/- 5% (P = 0.006). All fenamates inhibited GLYT1b currents; 100 microM flufenamic acid produced the most inhibition, decreasing the I (max) by 61 +/- 1% (P < 0.001). At 100 microM, effects on the GLYT2a I (max) were mixed: 13 +/- 2% inhibition by flufenamic acid (P = 0.002), 30 +/- 6% enhancement by niflumic acid (P = 0.002), and no effect by mefenamic acid. Minor effects on substrate affinity suggested non-competitive mechanisms. These data could contribute to the development of selective transport modulators.
Habjan
Suzanne
S
Discipline of Pharmacology, Bosch Institute, University of Sydney, Blackburn Building (D06), Sydney, NSW 2006, Australia.
Vandenberg
Robert J
RJ
D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005439:Flufenamic Acid / Q000737:chemistry / Q000494:pharmacology*; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D008528:Mefenamic Acid / Q000737:chemistry / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009544:Niflumic Acid / Q000737:chemistry / Q000494:pharmacology*; D014982:Xenopus laevis
D027322:Amino Acid Transport System X-AG; D050487:Glycine Plasma Membrane Transport Proteins; D008528:Mefenamic Acid; D009544:Niflumic Acid; D005439:Flufenamic Acid