We show that electroconvulsive therapy (ECT)-like stimulation greatly enhances synaptic potentiation induced by dopamine at the excitatory synapse formed by the hippocampal mossy fiber in mice. The effect of ECT-like stimulation on the dopaminergic modulation was rapidly induced, maintained for more than 4 wk after repeated treatments, and most likely mediated by increased expression of the dopamine D1 receptor. These effects may be relevant to fast-acting strong antidepressant action of ECT.
The selective PPARα modulator (SPPARMα) is expected to medicate dyslipidemia with minimizing adverse effects. Recently, pemafibrate was screened from the ligand library as an SPPARMα bearing strong potency. Several clinical pieces of evidence have proved the usefulness of pemafibrate as a medication; however, how pemafibrate works as a SPPARMα at the molecular level is not fully known. In this study, we investigate the molecular mechanism behind its novel SPPARMα character through a combination of approaches of X-ray crystallography, isothermal titration calorimetry (ITC), and fragment molecular orbital (FMO) analysis. ITC measurements have indicated that pemafibrate binds more strongly to PPARα than to PPARγ. The crystal structure of PPARα-ligand binding domain (LBD)/pemafibrate/steroid receptor coactivator-1 peptide (SRC1) determined at 3.2 Å resolution indicates that pemafibrate binds to the ligand binding pocket (LBP) of PPARα in a Y-shaped form. The structure also reveals that the conformation of the phenoxyalkyl group in pemafibrate is flexible in the absence of SRC1 coactivator peptide bound to PPARα; this gives a freedom for the phenoxyalkyl group to adopt structural changes induced by the binding of coactivators. FMO calculations have indicated that the accumulation of hydrophobic interactions provided by the residues at the LBP improve the interaction between pemafibrate and PPARα compared with the interaction between fenofibrate and PPARα.
Retinoid X receptor (RXR) heterodimers
such as PPAR/RXR, LXR/RXR,
and FXR/RXR can be activated by RXR agonists alone and are therefore
designated as permissive. Similarly, existing RXR antagonists show
allosteric antagonism toward partner receptor agonists in these permissive
RXR heterodimers. Here, we show 1-(3-(2-ethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylic acid (14, CBTF-EE) as the first RXR antagonist that does not show
allosteric inhibition in permissive RXR heterodimers. This compound
was designed based on the hypothesis that RXR antagonists that do
not induce conformational changes of RXR would not exhibit such allosteric
inhibition. CD spectra and X-ray co-crystallography of the complex
of 14 and the RXR ligand binding domain (LBD) confirmed
that 14 does not change the conformation of hRXR-LBD.
The X-ray structure analysis revealed that 14 binds at
the entrance of the ligand binding pocket (LBP), blocking access to
the LBP and thus serving as a “gatekeeper”.
Ligands for retinoid X receptors (RXRs), "rexinoids", are attracting interest as candidates for therapy of type 2 diabetes, Alzheimer's and Parkinson's diseases. However, current screening methods for rexinoids are slow and require special apparatus or facilities. Here, we created 7-hydroxy-2oxo-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2H-chromene-3-carboxylic acid (10, CU-6PMN) as a new fluorescent RXR agonist and developed a screening system of rexinoids using 10. Compound 10 was designed based on the fact that umbelliferone emits strong fluorescence in a hydrophilic environment, but the fluorescence intensity decreases in hydrophobic environments such as the interior of proteins. The developed assay using 10 enabled screening of rexinoids to be performed easily within a few hours by monitoring changes of fluorescence intensity with widely available fluorescence microplate readers, without the need for processes such as filtration.
Retinoid
X receptor (RXR) ligands often bind in modes in which
the carboxy group forms a hydrogen bond inside the ligand-binding
pocket (LBP). However, our previously reported RXR antagonist, CBTF-EE
(4a), binds with its carboxy group directed outside the
LBP and its alkoxy side chain located inside the LBP. Here, we examined
the binding modes of 4b and 4c bearing a
nitrobenzoxadiazole (NBD) or boron-dipyrromethene (BODIPY) fluorophore,
respectively, at the end of the alkoxy chain of 4a. Both
compounds function as RXR antagonists. 4c, but not 4b, was available for a fluorescence polarization binding
assay, indicating that rotation of BODIPY, but not NBD, is restricted
in the bound state. The fluorescence findings, supported by docking
simulations, suggest the fluorophores are located outside the LBP,
so that the binding mode of 4b and 4c is
different from that of 4a. The assay results were highly
correlated with those of a [3H]9-cis-retinoic
acid assay.
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