Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Eupafolin Suppresses P/Q-Type Ca2+ Channels to Inhibit Ca2+/Calmodulin-Dependent Protein Kinase II and Glutamate Release at Rat Cerebrocortical Nerve Terminals

  • Chang, Anna (School of Medicine, Fu Jen Catholic University) ;
  • Hung, Chi-Feng (School of Medicine, Fu Jen Catholic University) ;
  • Hsieh, Pei-Wen (Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology) ;
  • Ko, Horng-Huey (Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University) ;
  • Wang, Su-Jane (School of Medicine, Fu Jen Catholic University)
  • Received : 2021.03.09
  • Accepted : 2021.05.28
  • Published : 2021.11.01
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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/calmodulin-dependent 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

Acknowledgement

This work was supported by the Shin Kong Wu Ho-Su Memorial Hospital (grant no.108-SKH-FJU-01).

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