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A structural overview of G-protein-coupled receptors in neurological disorders

Acta Pharmacologica Sinica (2026)Cite this article

Abstract

Neuropsychiatry and neurodegenerative disorders (NPDs and NDDs) are often associated with various physiological factors. It is increasingly apparent that signal transducers like G-protein-coupled receptors (GPCRs) are critical in disease progression and constitute an important class of drug targets. Several members of class A, class B, and class C GPCR families, along with their cognate binding partners, are involved in neurotransmission and neuromodulation. The vast information about the different molecular states of these GPCRs with their signaling complexes unravels the understanding of residual specificity in these protein-protein interactions and the dynamicity of transmembrane helices. The atypical mode of interaction of GPCRs with binding partners provides valuable insights for GPCR-conformation-based drug designing. In this review, we highlight the structural features of the serotonin, dopamine, and corticotropin receptors, namely 5-HTR1A, 5-HTR1B, 5-HTR2A, 5-HTR2B, 5-HTR2C, 5-HTR4, 5-HTR6, 5-HTR7, D1-5R, and CRF1-2R when forming transient complexes with G-proteins and arrestins. The distinct structural characteristics of these receptors explain the underlying molecular mechanism for signaling specificity and related physiological processes. This review also summarizes the importance of these structural insights in developing newer and effective pharmacologically biased drugs that can mediate specific signaling pathways to GPCRs.

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Fig. 1: Canonical and non-canonical GPCR signaling.
Fig. 2: G-proteins regulating the PI3K/Akt signaling.
Fig. 3: A serotonin receptor may be involved in the pathogenesis of Alzheimer’s disease (AD).
Fig. 4: Critical residues in serotonin, dopamine, and corticotropin-releasing factor receptor families are involved in interaction with Gα proteins.
Fig. 5: GRK-binding modes with GPCRs.
Fig. 6: Cartoon representing the common orthosteric binding pocket for different drugs across various GPCRs and active and inactive TMD6 conformational transition.

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

    Oindrilla Dutta Gupta

  2. Department of Bio-Sciences, School of Bio Sciences and Technology (SBST), Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India

    Indranil Chakraborty & Kuntal Pal

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  1. Oindrilla Dutta Gupta
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KP – conceptualization, editing, and review of manuscript; ODG – writing and editing of original manuscript, formal analysis, preparation of images; IC – writing and editing of original manuscript, preparation of images. All authors contributed equally to the preparation of the manuscript.

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Dutta Gupta, O., Chakraborty, I. & Pal, K. A structural overview of G-protein-coupled receptors in neurological disorders. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-025-01712-6

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