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OptoH3R fusion protein mimics β-arrestin-mediated membrane endocytosis of histamine H3 receptor in vitro
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DOI：10.1186/s13041-026-01322-1.png)
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Abstract
En 中文
OptoH3R is an artificial fusion protein that combines the photosensitive elements of rhodopsin with the signaling domain of the histamine H3 receptor (H3R), enabling light-controlled activation of downstream H3R pathways. Although our previous study demonstrated that OptoH3R mimics the acute effects of H3R activation on neuronal activity, whether this tool can also recapitulate the long-term receptor desensitization and internalization processes associated with prolonged H3R activation remains unclear. In this study, primary cortical neurons and HeLa cells were employed to investigate the alterations in subcellular localization of OptoH3R upon sustained photoactivation, with histamine-stimulated wild-type (WT) H3R serving as a control. Furthermore, the role of β-arrestin in this process was explored. Time-lapse fluorescence imaging revealed that the number of puncta progressively increased over time following laser stimulation. Subsequent co-staining experiments with endosome marker EEA1 showed that 75.5% of light‑induced puncta were EEA1‑positive. Notably, the increase in OptoH3R-positive vesicles within neuronal cells was attenuated by the β-arrestin inhibitor barbadin, a pattern consistent with the internalization observed in histamine-stimulated WT H3R. Collectively, our findings demonstrate that OptoH3R recruits β-arrestin signaling upon sustained optical stimulation, thereby recapitulating H3R desensitization dynamics. This establishes OptoH3R as a useful tool for dissecting the spatiotemporally specific functions of H3R, including both its acute signaling and long-term β-arrestin-related mechanisms.
Keywords:
OptoH3R
β-arrestin pathway
Optogenetics
Cell signaling
Histamine H3 receptor
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