Evaluation of PhTX-74 as Subtype-Selective Inhibitor of GluA2-Containing AMPA Receptors
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Evaluation of PhTX-74 as Subtype-Selective Inhibitor of GluA2-Containing AMPA Receptors. / Poulsen, Mette Homann; Lucas, Simon; Strømgaard, Kristian; Kristensen, Anders Skov.
In: Molecular Pharmacology, Vol. 85, No. 2, 02.2014, p. 261-268.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Evaluation of PhTX-74 as Subtype-Selective Inhibitor of GluA2-Containing AMPA Receptors
AU - Poulsen, Mette Homann
AU - Lucas, Simon
AU - Strømgaard, Kristian
AU - Kristensen, Anders Skov
PY - 2014/2
Y1 - 2014/2
N2 - The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are glutamate-gated cation channels that mediate fast excitatory synaptic transmission in the central nervous system. AMPARs are tetramers formed by homo- or heteromeric assembly of GluA1-4 subunits to produce multiple subtypes with varying biophysical properties. Polyamine toxins such as joro spider toxins, philanthotoxins (PhTXs), 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 analog, 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 shows that PhTX-74 inhibits homomeric GluA1 and GluA3 receptors nonselectively, with IC50 values in the nanomolar range (252-356 nM), and heteromeric GluA1/A2 and GluA2/A3 receptors nonselectively, 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.
AB - The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are glutamate-gated cation channels that mediate fast excitatory synaptic transmission in the central nervous system. AMPARs are tetramers formed by homo- or heteromeric assembly of GluA1-4 subunits to produce multiple subtypes with varying biophysical properties. Polyamine toxins such as joro spider toxins, philanthotoxins (PhTXs), 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 analog, 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 shows that PhTX-74 inhibits homomeric GluA1 and GluA3 receptors nonselectively, with IC50 values in the nanomolar range (252-356 nM), and heteromeric GluA1/A2 and GluA2/A3 receptors nonselectively, 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.
KW - Faculty of Health and Medical Sciences
U2 - 10.1124/mol.113.089961
DO - 10.1124/mol.113.089961
M3 - Journal article
C2 - 24220009
VL - 85
SP - 261
EP - 268
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 2
ER -
ID: 94826539