4-Alkyl- and 4-Cinnamylglutamic Acid Analogues Are Potent GluR5 Kainate Receptor Agonists

Pedregal, Concepciòn; Collado, Iván; Escribano, Ana; Ezquerra, J.; Domı́nguez, Carmen; Mateo, Ana; Rubio, Alberto Pérez; Baker, Stephen; Goldsworthy, J.; Kamboj, Rajender K.; Ballyk, Barbara A.; Hoo, Ken H.; Bleakman, David

doi:10.1021/jm9911682

Cited by 36 publications

(34 citation statements)

References 20 publications

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“…The gammasubstituted glutamate analogues SYM2081 and LY339434 are also more selective for kainate than for AMPA receptors. Whereas the first displays selectivity for GluR5-and GluR6-containing kainate receptors, the latter seems more selective for GluR5 than for GluR6 and GluR7 (Small et al 1998;Pedregal et al 2000;Alt et al 2004). However, SYM2081 inhibits currents through kainate receptors by a process of fast agonist-induced desensitization (Zhou et al 1997) and thus essentially performs as an antagonist of these receptors.…”

Section: Kainate-receptor Agonistsmentioning

confidence: 97%

Kainate receptors

2006

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Kainate receptors form a family of ionotropic glutamate receptors that appear to play a special role in the regulation of the activity of synaptic networks. This review first describes briefly the molecular and pharmacological properties of native and recombinant kainate receptors. It then attempts to outline the general principles that appear to govern the function of kainate receptors in the activity of synaptic networks under physiological conditions. It subsequently describes the way that kainate receptors are involved in synaptic integration, synaptic plasticity, the regulation of neurotransmitter release and the control of neuronal excitability, and the manner in which they might play an important role in synaptogenesis and synaptic maturation. These functions require the proper subcellular localization of kainate receptors in specific functional domains of the neuron, necessitating complex cellular and molecular trafficking events. We show that our comprehension of these mechanisms is just starting to emerge. Finally, this review presents evidence that implicates kainate receptors in pathophysiological conditions such as epilepsy, excitotoxicity and pain, and that shows that these receptors represent promising therapeutic targets.

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Section: Kainate-receptor Agonistsmentioning

confidence: 97%

Kainate receptors

2006

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“…SYM2081 and LY339434 are gamma substituted glutamate analogues which are also selective for kainate over AMPA receptors. SYM2081 is active at both GluR5-and GluR6-containing receptors, whilst LY339434 is selective for GluR5 over GluR6 and GluR7 (Small et al 1998;Pedegral et al 2000;Alt et al 2004). …”

Section: Kainate Receptor Agonistsmentioning

confidence: 99%

Ionotropic and metabotropic glutamate receptor structure and pharmacology

2005

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Selective pharmacological tools have enabled the study of glutamate receptors. However, pharmacological coverage of the family is incomplete and considerable scope remains for the development of novel ligands, particularly those with in vivo utility, and for the their use together with existing tools for the further investigation of the roles of receptor family members in CNS function and as potentially novel therapeutics.

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“…This compound is in essence an alkylated version of glutamate and resembles the known iGluR6 agonist (2S,4R)-4-allyl glutamate (2; Fig. 2a) 15 . We have extended the allyl side chain of this compound to include a moiety that mimics half of an azobenzene.…”

Section: Synthesis and Evaluation Of A Tether Modelmentioning

confidence: 99%

Allosteric control of an ionotropic glutamate receptor with an optical switch

et al. 2005

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The precise regulation of protein activity is fundamental to life. The allosteric control of an active site by a remote regulatory binding site is a mechanism of regulation found across protein classes, from enzymes to motors to signaling proteins. We describe a general approach for manipulating allosteric control using synthetic optical switches. Our strategy is exemplified by a ligand-gated ion channel of central importance in neuroscience, the ionotropic glutamate receptor (iGluR). Using structure-based design, we have modified its ubiquitous clamshell-type ligand-binding domain to develop a light-activated channel, which we call LiGluR. An agonist is covalently tethered to the protein through an azobenzene moiety, which functions as the optical switch. The agonist is reversibly presented to the binding site upon photoisomerization, initiating clamshell domain closure and concomitant channel gating. Photoswitching occurs on a millisecond timescale, with channel conductances that reflect the photostationary state of the azobenzene at a given wavelength. Our device has potential uses not only in biology but also in bioelectronics and nanotechnology.Many proteins function like molecular machines that undergo mechanical movements in response to input signals. These signals can consist of changes in voltage, membrane tension, temperature or, most commonly, ligand concentration. Ligands provide information about events in the external world or about the energetic or biosynthetic state of the cell. They can be as small as a proton or as large as a whole protein. In allostery, ligand binding induces a structural change of a sensor domain, which propagates to a functional domain of the protein and alters its behavior. Such conformational control can operate over long distances, crossing a membrane or passing from one protein to another in a complex.Reengineering of nanoscopic protein machines to contain artificial control elements would be a major benefit for biology and technology. Optical switches would be especially powerful, as they could be activated remotely with precise temporal and spatial control 1,2 . A simple design Correspondence should be addressed to E.I. (ehud@berkeley.edu) and D.T. (trauner@berkeley.edu).. 5 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Chemical Biology website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript strategy would be to modify a protein by attaching a synthetic ligand whose binding ability could be altered by light. These ligands tethered via an optical switch could function in two ways. They could conditionally block the active site of an enzyme or the pore of a channel without inducing major conformational changes in the protein, or they could reversibly present an agonist to an allosteric binding site and conditionally trigger the normal conformational changes of ac...

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4-Alkyl- and 4-Cinnamylglutamic Acid Analogues Are Potent GluR5 Kainate Receptor Agonists

Cited by 36 publications

References 20 publications

Kainate receptors

Kainate receptors

Ionotropic and metabotropic glutamate receptor structure and pharmacology

Allosteric control of an ionotropic glutamate receptor with an optical switch

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