ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Neuropharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1588105
Exploration of the potential neurotransmitter or neuromodulator-like properties of harmine: Evidence from synthesis to synaptic modulation
Provisionally accepted
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
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The discovery of new neurotransmitters is crucial for the in-depth understanding of neural signal transmission, neurological disorders, and relevant treatment strategies. Emerging evidence has indicated that harmine is an important endogenous compound, and its level is closely related to different physiological and disease states. Inspired by this, we propose a hypothesis that harmine may be a potential neurotransmitter or neuromodulator and display neurotransmitter or neuromodulatorlike properties. This study aims to explore the potential properties of harmine as a neurotransmitter or neuromodulator according to the essential criteria. We investigated the synthesis, clearance, release, and receptor interactions of harmine in the central nervous system using recombinant protein expression, mass spectrometry analysis, and human proteome microarrays. Our study demonstrated that adipocyte plasma membrane-associated protein isoform X1 (APMAP-X1) could effectively catalyze the Pictet-Spengler reaction in mammals to generate tetrahydroharmine, which was subsequently oxidized by myeloperoxidase (MPO) to produce harmine. Moreover, synaptosome and cell experiments indicated that harmine could be metabolized, taken up, and released within the synaptic cleft, fulfilling the conditions for clearance and release within the synaptic cleft. Harmine also regulated the expression of neurotransmitter transporters, implying its potential neuromodulatory properties. Further investigation found that G protein-coupled receptor 85 (GPR85) and chloride intracellular channel 2 (CLIC2) were receptors targeted by harmine in the central nervous system. Functional verification results confirmed that harmine exerted an inhibitory effect on the GPR85 and could induce cellular depolarization. Current findings provide preliminary evidence that harmine may exhibit neurotransmitter-like properties in certain respects and support its role as an endogenous neuromodulator. However, direct evidence supporting harmine as a neurotransmitter remains limited. Further studies are needed to clarify the precise mechanisms of harmine in neurotransmission. Our study provides a new perspective for researchers on exploring novel endogenous molecules and their significance in neurophysiology.
Keywords: Harmine, neurotransmitter, Neuromodulator, adipocyte plasma membraneassociated protein, Central Nervous System, receptor interaction
Received: 05 Mar 2025; Accepted: 17 Jun 2025.
Copyright: © 2025 Xie, Cao, Li, Wang, Guan, Cheng and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Changhong Wang, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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