Dieckol is a natural positive allosteric modulator of GABA_A-benzodiazepine receptors and enhances inhibitory synaptic activity in cultured neurons

ABSTRACT

Phlorotannin supplement (PS) is a natural hypnotic substrate that modulates γ-aminobutyric acid type A (GABA_A)-benzodiazepine (BZD) receptors. However, there is a lack of functional data assessing the role of individual components of PS, such as Dieckol, as allosteric activators of GABA_A receptors (GABA_AR). Using the whole cell patch clamp technique, we demonstrated that PS functionally enhanced the activity of GABA_A-BZD receptors in a heterologous system and in primary cultured neurons. Application of diazepam (DZP) or Dieckol (1) increased GABA_AR-mediated inward current in HEK293T cells containing the α1 subunit in a dose-dependent manner, (2) which was blocked by co-treatment with the selective benzodiazepine site antagonist, flumazenil (FLZ); it also (3) increased the amplitude of GABA_A-BZD receptors in primary cultured neurons, which was blocked by FLZ and (4) attenuated spontaneous activity in cultured neurons. These results indicate that PS and Dieckol act as positive allosteric activators of GABA_A-BZD receptors, which might be the underlying mechanism of the sedative-hypnotic effect of PS. To our knowledge, this is the first study to directly link Dieckol-induced GABA_AR activation via the BZD site binding and suppression of spontaneous neuronal activity in vitro.

KEYWORDS:

• Dieckol
• phlorotannin
• GABAA-benzodiazepine receptor
• insomnia
• cultured neurons
• polyphenol
• therapeutic agent
• sleep

Acknowledgements

SK and JJ contributed equally to this work. SK, JJ, SC, and JL designed and contributed to manuscript drafting. JL managed the project. All authors reviewed the manuscript and approved the final version.

Disclosure statement

No potential conflict of interest was reported by the authors.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This research was supported by the Main Research Program (E0164503-03) of the Korea Food Research Institute funded by the Ministry of Science and ICT and a Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI17C0952).

Notes on contributors

Sangoh Kwon

Sangoh Kwon is Director of Research R&D center at S&D Research and Development Institute S&D Co., Ltd.

Jong Hoon Jung

Jong Hoon Jung is Researcher at Food Functional Evaluation Support Team, Korea Food Research Institute (KFRI).

Suengmok Cho

Seungmok Cho is Assistant Professor at the Department of Food Science and Technology, Pukyong National University.

Kwang-Deog Moon

Kwang-Deog Moon is Professor, Major in Food Biotechnology, School of Food Science & Biotechnology, Kyungpook National University.

Jaekwang Lee

Jaekwang Lee is a Senior Scientist at Research group of Functional Food Materials, Division of Food Functionality, Korea Food Research Institute (KFRI).