TY - JOUR T1 - Evaluation of Phtx-74 as Subtype-selective Inhibitor of Glua2-containing Ampa Receptors JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.113.089961 SP - mol.113.089961 AU - Mette H Poulsen AU - Simon Lucas AU - Kristian Stromgaard AU - Anders S Kristensen Y1 - 2013/01/01 UR - http://molpharm.aspetjournals.org/content/early/2013/11/12/mol.113.089961.abstract N2 - The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors are glutamate-gated cation channels that mediate fast excitatory synaptic transmission in the central nervous system (CNS). AMPARs are tetramers formed by homo- or heteromeric assembly of GluA1 to GluA4 subunits to produce multiple subtypes with varying biophysical properties. Polyamine toxins such as joro spider toxins, philanthotoxins and argiotoxins are use-dependent ion channel blockers of AMPARs widely employed as highly potent antagonists of GluA2-lacking receptor subtypes. In addition to this use, recent findings have indicated that a philanthotoxin analogue PhTX-74 can distinguish among GluA2-containing AMPAR subtypes in the presence of the prototypical transmembrane AMPAR regulatory protein γ-2 (or stargazin). Thus, PhTX-74 may be of potential use in studies of the neurobiological role of GluA2-containing subtypes. We have evaluated the pharmacological profile of PhTX-74 and related polyamine toxins at homo- and heteromeric AMPARs in the presence and absence of γ-2. Determination of IC50 values for inhibition of glutamate-evoked currents from Xenopus oocytes expressing recombinant homo- or heteromeric combinations of GluA1, GluA2 and GluA3 in the presence of γ-2 show that PhTX-74 inhibits homomeric GluA1 and GluA3 receptors non-selectively with IC50 values in the nanomolar range (252 to 356 nM), and heteromeric GluA1/A2 and GluA2/A3 receptors non-selectively with IC50 values in the micromolar range (22 μM). Thus, in contrast to earlier findings, we find that PhTX-74 cannot pharmacologically discriminate between GluA2-containing AMPAR subtypes. ER -