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Blocking Metabotropic Glutamate Receptor Subtype 7 (mGlu7) via the Venus Flytrap Domain (VFTD) Inhibits Amygdala Plasticity, Stress, and Anxiety-related Behavior

Overview of attention for article published in Journal of Biological Chemistry, April 2014
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Blocking Metabotropic Glutamate Receptor Subtype 7 (mGlu7) via the Venus Flytrap Domain (VFTD) Inhibits Amygdala Plasticity, Stress, and Anxiety-related Behavior
Published in
Journal of Biological Chemistry, April 2014
DOI 10.1074/jbc.m113.542654
Pubmed ID

Christine E. Gee, Daniel Peterlik, Christoph Neuhäuser, Rochdi Bouhelal, Klemens Kaupmann, Grit Laue, Nicole Uschold-Schmidt, Dominik Feuerbach, Kaspar Zimmermann, Silvio Ofner, John F. Cryan, Herman van der Putten, Markus Fendt, Ivo Vranesic, Ralf Glatthar, Peter J. Flor


The metabotropic glutamate receptor subtype 7 (mGlu7) is an important presynaptic regulator of neurotransmission in the mammalian CNS. mGlu7 function has been linked to autism, drug abuse, anxiety, and depression. Despite this, it has been difficult to develop specific blockers of native mGlu7 signaling in relevant brain areas such as amygdala and limbic cortex. Here, we present the mGlu7-selective antagonist 7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one (XAP044), which inhibits lateral amygdala long term potentiation (LTP) in brain slices from wild type mice with a half-maximal blockade at 88 nm. There was no effect of XAP044 on LTP of mGlu7-deficient mice, indicating that this pharmacological effect is mGlu7-dependent. Unexpectedly and in contrast to all previous mGlu7-selective drugs, XAP044 does not act via the seven-transmembrane region but rather via a binding pocket localized in mGlu7's extracellular Venus flytrap domain, a region generally known for orthosteric agonist binding. This was shown by chimeric receptor studies in recombinant cell line assays. XAP044 demonstrates good brain exposure and wide spectrum anti-stress and antidepressant- and anxiolytic-like efficacy in rodent behavioral paradigms. XAP044 reduces freezing during acquisition of Pavlovian fear and reduces innate anxiety, which is consistent with the phenotypes of mGlu7-deficient mice, the results of mGlu7 siRNA knockdown studies, and the inhibition of amygdala LTP by XAP044. Thus, we present an mGlu7 antagonist with a novel molecular mode of pharmacological action, providing significant application potential in psychiatry. Modeling the selective interaction between XAP044 and mGlu7's Venus flytrap domain, whose three-dimensional structure is already known, will facilitate future drug development supported by computer-assisted drug design.

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Mendeley readers

The data shown below were compiled from readership statistics for 95 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 1%
Germany 1 1%
Ireland 1 1%
Unknown 92 97%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 22 23%
Researcher 13 14%
Student > Master 12 13%
Student > Bachelor 12 13%
Student > Doctoral Student 4 4%
Other 11 12%
Unknown 21 22%
Readers by discipline Count As %
Neuroscience 16 17%
Agricultural and Biological Sciences 13 14%
Biochemistry, Genetics and Molecular Biology 10 11%
Chemistry 10 11%
Psychology 8 8%
Other 15 16%
Unknown 23 24%