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Understanding the Molecular Regulation of Serotonin Receptor 5-HTR1B-β-Arrestin1 Complex in Stress and Anxiety Disorders

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Abstract

The serotonin receptor subtype 5-HTR1B is widely distributed in the brain with an important role in various behavioral implications including neurological conditions and psychiatric disorders. The neuromodulatory action of 5-HTR1B largely depends upon its arrestin mediated signaling pathway. In this study, we tried to investigate the role of unusually long intracellular loop 3 (ICL3) region of the serotonin receptor 5-HTR1B in interaction with β-arrestin1 (Arr2) to compensate for the absence of the long cytoplasmic tail. Molecular modeling and docking tools were employed to obtain a suitable molecular conformation of the ICL3 region in complex with Arr2 which dictates the specific complex formation of 5-HTR1B with Arr2. This reveals the novel molecular mechanism of phosphorylated ICL3 mediated GPCR-arrestin interaction in the absence of the long cytoplasmic tail. The in-cell disulfide cross-linking experiments and molecular dynamics simulations of the complex further validate the model of 5-HTR1B-ICL3-Arr2 complex. Two serine residues (Ser281 and Ser295) within the 5-HTR1B-ICL3 region were found to be occupying the electropositive pocket of Arr2 in our model and might be crucial for phosphorylation and specific Arr2 binding. The alignment studies of these residues showed them to be conserved only across 5-HTR1B mammalian species. Thus, our studies were able to predict a molecular conformation of 5-HTR1B-Arr2 and identify the role of long ICL3 in the signaling process which might be crucial in designing targeted drugs (biased agonists) that promote GPCR-Arr2 signaling to deter the effects of stress and anxiety-like disorders.

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The supporting data for this study is present in the supplementary file of the manuscript.

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Acknowledgements

We are thankful to Professor Eitan Reuveny of the Department of Biomolecular Sciences at the Weizmann Institute of Science, Israel, for providing us the technical support to perform the 100-ns MD simulation of the receptor-arrestin complex. Their institute’s facility was instrumental in the success of our research. We would also like to express our gratitude towards all the web servers and free open-access software used in this study. All illustrations have been created/edited using https://www.biorender.com/.

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Authors and Affiliations

  1. Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, 700126, Kolkata, West Bengal, India

    Oindrilla Dutta Gupta & Kuntal Pal

  2. Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001, Rehovot, Israel

    Izhar Karbat

  3. School of Biosciences and Technology (SBST), Vellore Institute of Technology, 632014, Vellore, Tamil Nadu, India

    Kuntal Pal

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  1. Oindrilla Dutta Gupta
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Contributions

Kuntal Pal—conceptualization, methodology, formal investigation, supervision, writing: evaluation and editing, authentication. Oindrilla Dutta Gupta—methodology, conceptualization, investigation, validation, data organization and writing: original draft. Izhar Karbat—experimental support with the 100-ns MD simulations.

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Correspondence to Kuntal Pal.

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Dutta Gupta, O., Karbat, I. & Pal, K. Understanding the Molecular Regulation of Serotonin Receptor 5-HTR1B-β-Arrestin1 Complex in Stress and Anxiety Disorders. J Mol Neurosci 73, 664–677 (2023). https://doi.org/10.1007/s12031-023-02146-7

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