Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2021.046
Eupafolin Suppresses P/Q-Type Ca2+ Channels to Inhibit Ca2+/ Calmodulin-Dependent Protein Kinase II and Glutamate Release at Rat Cerebrocortical Nerve Terminals
Anna Chang1,2, Chi-Feng Hung1, Pei-Wen Hsieh3,4,5, Horng-Huey Ko6,7 and Su-Jane Wang1,3,*
1School of Medicine, Fu Jen Catholic University, New Taipei City 24205
2Department of Neurology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 22060
3Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33303
4Graduate Institute of Natural Products, School of Traditional Chinese Medicine, and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33303
5Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou 33305
6Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708
7Drug Development and Value Creation Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
E-mail: med0003@mail.fju.edu.tw
Tel: +886-2-29053465, Fax: +886-2-29052096
Received: March 9, 2021; Revised: May 4, 2021; Accepted: May 28, 2021; Published online: September 3, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Eupafolin, a constituent of the aerial parts of Phyla nodiflora, has neuroprotective property. Because reducing the synaptic release of glutamate is crucial to achieving pharmacotherapeutic effects of neuroprotectants, we investigated the effect of eupafolin on glutamate release in rat cerebrocortical synaptosomes and explored the possible mechanism. We discovered that eupafolin depressed 4-aminopyridine (4-AP)-induced glutamate release, and this phenomenon was prevented in the absence of extracellular calcium. Eupafolin inhibition of glutamate release from synaptic vesicles was confirmed through measurement of the release of the fluorescent dye FM 1-43. Eupafolin decreased 4-AP-induced [Ca2+]i elevation and had no effect on synaptosomal membrane potential. The inhibition of P/Q-type Ca2+ channels reduced the decrease in glutamate release that was caused by eupafolin, and docking data revealed that eupafolin interacted with P/Q-type Ca2+ channels. Additionally, the inhibition of calcium/calmodulindependent protein kinase II (CaMKII) prevented the effect of eupafolin on evoked glutamate release. Eupafolin also reduced the 4-AP-induced activation of CaMK II and the subsequent phosphorylation of synapsin I, which is the main presynaptic target of CaMKII. Therefore, eupafolin suppresses P/Q-type Ca2+ channels and thereby inhibits CaMKII/synapsin I pathways and the release of glutamate from rat cerebrocortical synaptosomes.
Keywords: Eupafolin, Glutamate release, P/Q-type Ca2+ channels, CaMKII, Synapsin I, Cerebrocortical synaptosomes


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