Artemisinin is derived from the leaves and flowers of the annual mugwort (Artemisia annua) and has been used in traditional Chinese medicine for centuries. Artemisinin and its semi-synthetic derivatives - collectively known as artemisinins - are used to treat the tropical infectious disease malaria. In addition, these molecules also influence multiple cellular processes in humans. For example, artemisinins are able to activate the immune system against several types of cancer or to regulate the differentiation of pancreatic T cells, which could potentially be useful in the therapy of diabetes.
"Although this clinically-approved drug class is well established and has been used in some extent for centuries, it was unclear which molecular mechanisms underlie the corresponding cellular activities, such as target protein rfhumecognition and modulation," explains the first author of this published in the journal Neuron.
The structural biologist was the first to solve the crystal structures of two different artemisinin derivatives - artesunate and artemether - in a complex with gephyrin at 1.5-Å resolution. By binding to inhibitory glycine and GABAA receptors, gephyrin acts as a central scaffold protein of inhibitory postsynapses in the mammalian central nervous system. Gephyrin has only recently been identified as an artemisinin target protein.
Electrophysiological recordings reveal a significant inhibition of gephyrin-mediated neurotransmission by artemisinins. Furthermore, clustering analyses in primary neurons demonstrate a rapid inhibition and a time-dependent regulation of gephyrin and GABA AR cluster parameters.
The results clearly demonstrate how artemisinins target the universal receptor binding pocket in gephyrin and compete with the inhibitory neurotransmitter receptors for an overlapping binding site. These new findings could thus also serve as an effective tool to understand the physiology of the human brain.
Mechanism of action of anti-malaria drug in the brain
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