Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement
Abstract Agonistic profiles of AMPA receptor (AMPA-R) potentiators may be associated with seizure risk and bell-shaped dose-response effects. Here, we report the pharmacological characteristics of a novel AMPA-R potentiator, TAK-653, which exhibits minimal agonistic properties. TAK-653 bound to the...
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Nature Portfolio
2021
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oai:doaj.org-article:0d63b239f564462aba95ccd87d5032572021-12-02T15:33:00ZStrictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement10.1038/s41598-021-93888-02045-2322https://doaj.org/article/0d63b239f564462aba95ccd87d5032572021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93888-0https://doaj.org/toc/2045-2322Abstract Agonistic profiles of AMPA receptor (AMPA-R) potentiators may be associated with seizure risk and bell-shaped dose-response effects. Here, we report the pharmacological characteristics of a novel AMPA-R potentiator, TAK-653, which exhibits minimal agonistic properties. TAK-653 bound to the ligand binding domain of recombinant AMPA-R in a glutamate-dependent manner. TAK-653 strictly potentiated a glutamate-induced Ca2+ influx in hGluA1i-expressing CHO cells through structural interference at Ser743 in GluA1. In primary neurons, TAK-653 augmented AMPA-induced Ca2+ influx and AMPA-elicited currents via physiological AMPA-R with little agonistic effects. Interestingly, TAK-653 enhanced electrically evoked AMPA-R-mediated EPSPs more potently than AMPA (agonist) or LY451646 (AMPA-R potentiator with a prominent agonistic effect) in brain slices. Moreover, TAK-653 improved cognition for both working memory and recognition memory, while LY451646 did so only for recognition memory, and AMPA did not improve either. These data suggest that the facilitation of phasic AMPA-R activation by physiologically-released glutamate is the key to enhancing synaptic and cognitive functions, and nonselective activation of resting AMPA-Rs may negatively affect this process. Importantly, TAK-653 had a wide safety margin against convulsion; TAK-653 showed a 419-fold (plasma Cmax) and 1017-fold (AUC plasma) margin in rats. These findings provide insight into a therapeutically important aspect of AMPA-R potentiation.Atsushi SuzukiAkiyoshi KunugiYasukazu TajimaNoriko SuzukiMotohisa SuzukiMasashi ToyofukuHaruhiko KunoSatoshi SogabeYohei KosugiYasuyuki AwasakiTomohiro KakuHaruhide KimuraNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021) |
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Medicine R Science Q |
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Medicine R Science Q Atsushi Suzuki Akiyoshi Kunugi Yasukazu Tajima Noriko Suzuki Motohisa Suzuki Masashi Toyofuku Haruhiko Kuno Satoshi Sogabe Yohei Kosugi Yasuyuki Awasaki Tomohiro Kaku Haruhide Kimura Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement |
| description |
Abstract Agonistic profiles of AMPA receptor (AMPA-R) potentiators may be associated with seizure risk and bell-shaped dose-response effects. Here, we report the pharmacological characteristics of a novel AMPA-R potentiator, TAK-653, which exhibits minimal agonistic properties. TAK-653 bound to the ligand binding domain of recombinant AMPA-R in a glutamate-dependent manner. TAK-653 strictly potentiated a glutamate-induced Ca2+ influx in hGluA1i-expressing CHO cells through structural interference at Ser743 in GluA1. In primary neurons, TAK-653 augmented AMPA-induced Ca2+ influx and AMPA-elicited currents via physiological AMPA-R with little agonistic effects. Interestingly, TAK-653 enhanced electrically evoked AMPA-R-mediated EPSPs more potently than AMPA (agonist) or LY451646 (AMPA-R potentiator with a prominent agonistic effect) in brain slices. Moreover, TAK-653 improved cognition for both working memory and recognition memory, while LY451646 did so only for recognition memory, and AMPA did not improve either. These data suggest that the facilitation of phasic AMPA-R activation by physiologically-released glutamate is the key to enhancing synaptic and cognitive functions, and nonselective activation of resting AMPA-Rs may negatively affect this process. Importantly, TAK-653 had a wide safety margin against convulsion; TAK-653 showed a 419-fold (plasma Cmax) and 1017-fold (AUC plasma) margin in rats. These findings provide insight into a therapeutically important aspect of AMPA-R potentiation. |
| format |
article |
| author |
Atsushi Suzuki Akiyoshi Kunugi Yasukazu Tajima Noriko Suzuki Motohisa Suzuki Masashi Toyofuku Haruhiko Kuno Satoshi Sogabe Yohei Kosugi Yasuyuki Awasaki Tomohiro Kaku Haruhide Kimura |
| author_facet |
Atsushi Suzuki Akiyoshi Kunugi Yasukazu Tajima Noriko Suzuki Motohisa Suzuki Masashi Toyofuku Haruhiko Kuno Satoshi Sogabe Yohei Kosugi Yasuyuki Awasaki Tomohiro Kaku Haruhide Kimura |
| author_sort |
Atsushi Suzuki |
| title |
Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement |
| title_short |
Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement |
| title_full |
Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement |
| title_fullStr |
Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement |
| title_full_unstemmed |
Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement |
| title_sort |
strictly regulated agonist-dependent activation of ampa-r is the key characteristic of tak-653 for robust synaptic responses and cognitive improvement |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/0d63b239f564462aba95ccd87d503257 |
| work_keys_str_mv |
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1718387127132094464 |