Philanthotoxin 74

Philanthotoxin 74 dihydrochloride (PhTx 74) is an AMPAR antagonist; inhibits GluR3 and GluR1 with IC50s of 263 and 296 nM, respectively.

In Vitro:Philanthotoxin 74 in the micromolar concentration range displays selective inhibition between the two major subtypes of GluA2R-containing AMPARs, GluA1/A2R and GluA2R/A3, when these are coexpressed with γ-2 in oocytes. Philanthotoxin 74 is reported to fully inhibit GluA1/A2R receptors when applied at a concentration of 500 μM while producing 10% inhibition at GluA2R/A3 receptors. Philanthotoxin 74, when tested at concentrations of 100 and 500 μM, displays pronounced channel block (more than 80%) of GluA1/A2R but minimal block (less than 10%) of GluA2R/A3. Oocytes expressing GluA2R alone that homomeric GluA2R is virtually inert to philanthotoxin 74 in the 0.1-300 μM concentration range, displaying less than 5% inhibition at the maximum tested concentration of 300 μM. Philanthotoxin 74 inhibits these receptors nonselectively, with IC50 values of about 30 μM, in both the presence and absence of γ-2[1].

References:
[1]. Poulsen MH, et al. Evaluation of PhTX-74 as subtype-selective inhibitor of GluA2-containing AMPA receptors. Mol Pharmacol. 2014 Feb;85(2):261-8. [2]. Kromann H, et al. Solid-phase synthesis of polyamine toxin analogues: potent and selective antagonists of Ca2+-permeable AMPA receptors. J Med Chem. 2002 Dec 19;45(26):5745-54.

Removal of synaptic Ca(2)+-permeable AMPA receptors during sleep.[Pubmed:21411638]

J Neurosci. 2011 Mar 16;31(11):3953-61.

There is accumulating evidence that sleep contributes to memory formation and learning, but the underlying cellular mechanisms are incompletely understood. To investigate the impact of sleep on excitatory synaptic transmission, we obtained whole-cell patch-clamp recordings from layer V pyramidal neurons in acute slices of somatosensory cortex of juvenile rats (postnatal days 21-25). In animals after the dark period, Philanthotoxin 74 (PhTx)-sensitive calcium-permeable AMPA receptors (CP-AMPARs) accounted for approximately 25% of total EPSP size, and current-voltage (I-V) relationships of the underlying EPSCs showed inward rectification. In contrast, in similar experiments after the light period, EPSPs were PhTx insensitive with linear I-V characteristics, indicating that CP-AMPARs were less abundant. Combined EEG and EMG recordings confirmed that slow-wave sleep-associated delta wave power peaked at the onset of the more quiescent, lights-on phase of the cycle. Subsequently, we show that burst firing, a characteristic action potential discharge mode of layer V pyramidal neurons during slow-wave sleep has a dual impact on synaptic AMPA receptor composition: repetitive burst firing without synaptic stimulation eliminated CP-AMPARs by activating serine/threonine phosphatases. Additionally, repetitive burst-firing paired with EPSPs led to input-specific long-term depression (LTD), affecting Ca(2+) impermeable AMPARs via protein kinase C signaling. In agreement with two parallel mechanisms, simple bursts were ineffective after the light period but paired bursts induced robust LTD. In contrast, incremental LTD was generated by both conditioning protocols after the dark cycle. Together, our results demonstrate qualitative changes at neocortical glutamatergic synapses that can be induced by discharge patterns characteristic of non-rapid eye movement sleep.

Evaluation of PhTX-74 as subtype-selective inhibitor of GluA2-containing AMPA receptors.[Pubmed:24220009]

Mol Pharmacol. 2014 Feb;85(2):261-8.

The alpha-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 gamma-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 gamma-2. Determination of IC(50) 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 gamma-2 shows that PhTX-74 inhibits homomeric GluA1 and GluA3 receptors nonselectively, with IC(50) values in the nanomolar range (252-356 nM), and heteromeric GluA1/A2 and GluA2/A3 receptors nonselectively, with IC(50) values in the micromolar range (22 muM). Thus, in contrast to earlier findings, we find that PhTX-74 cannot pharmacologically discriminate between GluA2-containing AMPAR subtypes.

Philanthotoxin 74 dihydrochloride (PhTx 74) is an AMPAR antagonist; inhibits GluR3 and GluR1 with IC50s of 263 and 296 nM, respectively.

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