5-HT7 Receptors: New Horizons in the Therapy of Neuropsychiatric and Neurodegenerative Diseases

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Abstract

The 5-HT₇ receptor, one of the most recently discovered members of the serotonin receptor family, plays a pivotal role in regulating central nervous system processes. Over the past three decades, substantial research has provided insights into its gene, expression patterns, molecular structure, and pharmacological properties. The 5-HT₇ receptor is involved in thermoregulation, sleep, circadian rhythms, and mood regulation, attracting increasing attention as a promising target for the treatment of depressive disorders, Alzheimer’s disease, and Parkinson’s disease. In this review, based on a systematic analysis of publications from 1993–2024, with a predominant focus on studies from the last decade in PubMed, Scopus and Web of Science databases, we provide an in-depth discussion of the functional characteristics of the 5-HT₇ receptor, its pharmacological profile, and current hypothetical models and molecular interactions that enhance our understanding of its unique role in neurophysiological regulation. Special attention is given to the therapeutic potential of the 5-HT₇ receptor in neuropsychiatric and neurodegenerative diseases.

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About the authors

A. Ya. Rodnyy

Institute of Cytology and Genetics, Siberian Branch of RAS

Author for correspondence.
Email: aleksandr1994rodny@gmail.com
Russian Federation, Novosibirsk

V. S. Naumenko

Institute of Cytology and Genetics, Siberian Branch of RAS

Email: aleksandr1994rodny@gmail.com
Russian Federation, Novosibirsk

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2. Fig. 1. Structure of the 5-HT₇ receptor. (a) Predicted structure of the human 5-HT₇ receptor (AF-P34969-F1-model-v4) using the AlphaFold neural network [49, 50]. (b) Structure of the human 5-HT₇ receptor (PDB ID: P34969) and the G protein subunit complex determined by cryo-electron microscopy [51, 52]. (c) The difference in the length of TM5 and TM6 regulates the receptor's preference for Gₛ or Gᵢ proteins.

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3. Fig. 2. Schematic representation of the signaling pathways regulated by the 5-HT₇ receptor. Gₛ protein-mediated effects are shown on the left. A summary of G₁₂ protein-mediated signaling processes is shown on the right. Abbreviations: AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; ERK1/2, extracellular signal-regulated kinases; Akt, protein kinase B, Hsp90, heat shock protein 90; ERM, ezrin-radixin-moesin family proteins; GEF, guanine nucleotide exchange factor; nRTK, non-receptor tyrosine kinases; mTOR, mammalian target of rapamycin; AKAPs, A-anchoring proteins. ZO – tight junction proteins; SRF – serum response factor; SRE – serum response element. Adapted from [54] with modifications.

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4. Fig. 3. Mechanisms of expression regulation and post-translational modification of the 5-HT₇ receptor. Transcription factors Sp1 and Sp3 activate HTR7 gene expression through the GC-rich promoter region. The SNP variant rs7905446 (GG/TG) enhances transcription. MicroRNA-29a (miR-29a) reduces the level of HTR7 mRNA, suppressing receptor expression. Post-translational modifications include phosphorylation, N-glycosylation, and palmitoylation and affect the functional activity of the receptor.

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5. Fig. 4. Physiological meaning of heterodimerization of 5-HT1A and 5-HT₇ receptors in the midbrain. Under physiological conditions, a balance is maintained between 5-HT1A/5-HT1A homodimers and 5-HT1A/5-HT₇ heterodimers, which ensures normal serotonin levels. In depression, an imbalance in the dimer structure is observed, with a predominance of 5-HT1A/5-HT1A homodimers, leading to a decrease in the serotonin level in the synaptic cleft. Overexpression of 5-HT₇ receptors increases the number of 5-HT1A/5-HT₇ heterodimers, which promotes inhibition of presynaptic 5-HT1A receptors, an increase in serotonin levels, and the implementation of the antidepressant effect. Translated from [13].

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