# HTR5A

## Overview
The HTR5A gene encodes the 5-hydroxytryptamine receptor 5A (5-HT5A), a member of the G protein-coupled receptor (GPCR) family, which plays a significant role in serotonin neurotransmission. This receptor is primarily expressed in the central nervous system and is involved in modulating various physiological processes, including mood regulation, cognition, and circadian rhythms. The 5-HT5A receptor is characterized by its unique structural features, such as a kinked TM5 helix and a bending TM4, which are essential for its activation and interaction with ligands (Zhang2022Inactive). Functionally, it couples with Gi/Go proteins, leading to the inhibition of adenylate cyclase and a decrease in cyclic adenosine monophosphate (cAMP) levels, thereby influencing neuronal excitability and synaptic transmission (Francken1998The; Barnes2020International). The receptor's distribution in brain regions such as the cerebral cortex, hippocampus, and cerebellum underscores its involvement in high cortical and limbic functions (Pasqualetti1998Distribution). Variants in the HTR5A gene have been associated with psychiatric disorders and metabolic traits, highlighting its clinical significance (Zhang2010Serotonin; Guan2016Evaluation).

## Structure
The HTR5A gene encodes the 5-HT5A receptor, a member of the G protein-coupled receptor (GPCR) family, which is involved in serotonin neurotransmission. The primary structure of the 5-HT5A receptor consists of a sequence of amino acids that form the receptor protein. Its secondary structure is characterized by the presence of alpha helices, which are typical of GPCRs (Levit2022StructureBased). The tertiary structure involves the arrangement of these helices within the cell membrane, contributing to the receptor's functional conformation (Zhang2022Inactive).

The 5-HT5A receptor has unique structural features, such as a kinked TM5 helix and a bending TM4, which are not commonly found in other serotonin receptors. These features are crucial for its activation and interaction with ligands (Zhang2022Inactive). The receptor's quaternary structure involves its interaction with G proteins, specifically the miniGo protein, which is essential for signal transduction (Zhang2022Inactive).

Post-translational modifications of the 5-HT5A receptor may include phosphorylation and glycosylation, which are common in GPCRs and can affect receptor function and signaling (Levit2022StructureBased). The receptor's unique sequence and structural characteristics contribute to its distinct pharmacological profile and ligand recognition (Zhang2022Inactive).

## Function
The HTR5A gene encodes the 5-HT5A receptor, a subtype of serotonin receptor that is primarily expressed in the central nervous system. This receptor is a G protein-coupled receptor (GPCR) that is involved in neurotransmission and modulates various physiological processes. In healthy human cells, the 5-HT5A receptor is known to couple with pertussis toxin-sensitive Gi/Go proteins, leading to the inhibition of adenylate cyclase activity and a subsequent decrease in cyclic adenosine monophosphate (cAMP) levels (Francken1998The; Barnes2020International). This signaling pathway is crucial for modulating neuronal excitability and synaptic transmission, impacting processes such as mood regulation, cognition, and circadian rhythms (THOMAS20065ht5A).

The receptor is widely distributed in the brain, with significant expression in regions such as the cerebral cortex, hippocampus, and cerebellum, suggesting its involvement in high cortical and limbic functions (Pasqualetti1998Distribution). The 5-HT5A receptor also activates inwardly rectifying potassium (K+) channels, which further influences neuronal activity (Grailhe2001Human). Despite its established roles, the precise physiological functions of the 5-HT5A receptor in humans remain not fully understood, necessitating further research to elucidate its contributions to brain function and behavior (Barnes2020International).

## Clinical Significance
The HTR5A gene, encoding the 5-hydroxytryptamine receptor 5A, has been implicated in several psychiatric disorders. Variants in HTR5A are associated with schizophrenia, particularly the single nucleotide polymorphism (SNP) rs1800883, which has been linked to impaired executive function in patients with schizophrenia (Guan2016Evaluation). This SNP is also associated with differences in cognitive performance, with C allele carriers showing better executive function compared to those with the G risk allele (Guan2016Evaluation). The gene has also been associated with major depressive disorder and bipolar disorder, suggesting shared genetic risk factors among these conditions (Guan2016Evaluation).

In addition to psychiatric disorders, HTR5A variants have been linked to metabolic traits. Specific SNPs in the HTR5A gene, such as rs3734967, are associated with increased plasma triglyceride levels, indicating a potential role in lipid metabolism (Zhang2010Serotonin). These genetic variations may influence the expression of HTR5A, affecting metabolic regulation and contributing to conditions like obesity and metabolic syndrome (Zhang2010Serotonin). The gene's expression is brain-specific, complicating direct measurement of its impact on plasma triglyceride levels (Zhang2010Serotonin).

## Interactions
The HTR5A gene encodes the 5-HT5A receptor, a G protein-coupled receptor that interacts with various proteins to mediate intracellular signaling pathways. The 5-HT5A receptor primarily couples with the Gi/o family of G proteins, which are involved in inhibiting adenylate cyclase activity, thereby reducing the levels of cyclic AMP in cells (Zhang2022Inactive; Tan2022Structural). The receptor forms a complex with Gαi, Gβ1, and Gγ2 subunits, which is crucial for its function and was studied using cryo-electron microscopy to reveal the structural details of these interactions (Tan2022Structural).

The receptor's interaction with G proteins involves specific structural interfaces, including transmembrane helices TM3, TM5, TM6, and the TM7-helix 8 junction, as well as the intracellular loop 2 (ICL2) (Tan2022Structural). These interactions are essential for the receptor's ability to couple with G proteins and initiate downstream signaling. The 5-HT5A receptor also interacts with the miniGo protein, a G protein subunit, which has been used to study the receptor's active state and its interactions with different G protein subunits (Zhang2022Inactive). These interactions are critical for understanding the receptor's role in neurotransmission and its potential as a therapeutic target.


## References


[1. (Francken1998The) Bart J.B. Francken, Mirek Jurzak, Jurgen F.M. Vanhauwe, Walter H.M.L. Luyten, and Josée E. Leysen. The human 5-ht5a receptor couples to gi/go proteins and inhibits adenylate cyclase in hek 293 cells. European Journal of Pharmacology, 361(2–3):299–309, November 1998. URL: http://dx.doi.org/10.1016/s0014-2999(98)00744-4, doi:10.1016/s0014-2999(98)00744-4. This article has 61 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/s0014-2999(98)00744-4)

[2. (Guan2016Evaluation) Fanglin Guan, Huali Lin, Gang Chen, Lu Li, Teng Chen, Xinshe Liu, Jiuqiang Han, and Tao Li. Evaluation of association of common variants in htr1a and htr5a with schizophrenia and executive function. Scientific Reports, November 2016. URL: http://dx.doi.org/10.1038/srep38048, doi:10.1038/srep38048. This article has 51 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/srep38048)

[3. (Levit2022StructureBased) Anat Levit Kaplan, Ryan T. Strachan, Joao M. Braz, Veronica Craik, Samuel Slocum, Thomas Mangano, Vanessa Amabo, Henry O’Donnell, Parnian Lak, Allan I. Basbaum, Bryan L. Roth, and Brian K. Shoichet. Structure-based design of a chemical probe set for the 5-ht5a serotonin receptor. Journal of Medicinal Chemistry, 65(5):4201–4217, February 2022. URL: http://dx.doi.org/10.1021/acs.jmedchem.1c02031, doi:10.1021/acs.jmedchem.1c02031. This article has 21 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1021/acs.jmedchem.1c02031)

[4. (Zhang2010Serotonin) Y. Zhang, E. M. Smith, T. M. Baye, J. V. Eckert, L. J. Abraham, E. K. Moses, A. H. Kissebah, L. J. Martin, and M. Olivier. Serotonin (5-ht) receptor 5a sequence variants affect human plasma triglyceride levels. Physiological Genomics, 42(2):168–176, July 2010. URL: http://dx.doi.org/10.1152/physiolgenomics.00038.2010, doi:10.1152/physiolgenomics.00038.2010. This article has 31 citations and is from a peer-reviewed journal.](https://doi.org/10.1152/physiolgenomics.00038.2010)

[5. (Grailhe2001Human) Régis Grailhe, Gregg W Grabtree, and René Hen. Human 5-ht5 receptors: the 5-ht5a receptor is functional but the 5-ht5b receptor was lost during mammalian evolution. European Journal of Pharmacology, 418(3):157–167, April 2001. URL: http://dx.doi.org/10.1016/s0014-2999(01)00933-5, doi:10.1016/s0014-2999(01)00933-5. This article has 91 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/s0014-2999(01)00933-5)

[6. (Zhang2022Inactive) Shicheng Zhang, He Chen, Chengwei Zhang, Ying Yang, Petr Popov, Jing Liu, Brian E. Krumm, Can Cao, Kuglae Kim, Yan Xiong, Vsevolod Katritch, Brian K. Shoichet, Jian Jin, Jonathan F. Fay, and Bryan L. Roth. Inactive and active state structures template selective tools for the human 5-ht5a receptor. Nature Structural & Molecular Biology, 29(7):677–687, July 2022. URL: http://dx.doi.org/10.1038/s41594-022-00796-6, doi:10.1038/s41594-022-00796-6. This article has 20 citations.](https://doi.org/10.1038/s41594-022-00796-6)

[7. (Barnes2020International) Nicholas M. Barnes, Gerard P. Ahern, Carine Becamel, Joël Bockaert, Michael Camilleri, Severine Chaumont-Dubel, Sylvie Claeysen, Kathryn A. Cunningham, Kevin C. Fone, Michael Gershon, Giuseppe Di Giovanni, Nathalie M. Goodfellow, Adam L. Halberstadt, Rachel M. Hartley, Ghérici Hassaine, Katharine Herrick-Davis, Ruud Hovius, Enza Lacivita, Evelyn K. Lambe, Marcello Leopoldo, Finn Olav Levy, Sarah C. R. Lummis, Philippe Marin, Luc Maroteaux, Andrew C. McCreary, David L. Nelson, John F. Neumaier, Adrian Newman-Tancredi, Hugues Nury, Alexander Roberts, Bryan L. Roth, Anne Roumier, Gareth J. Sanger, Milt Teitler, Trevor Sharp, Carlos M. Villalón, Horst Vogel, Stephanie W. Watts, and Daniel Hoyer. International union of basic and clinical pharmacology. cx. classification of receptors for 5-hydroxytryptamine; pharmacology and function. Pharmacological Reviews, 73(1):310–520, December 2020. URL: http://dx.doi.org/10.1124/pr.118.015552, doi:10.1124/pr.118.015552. This article has 158 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1124/pr.118.015552)

[8. (THOMAS20065ht5A) D THOMAS. 5-ht5a receptors as a therapeutic target. Pharmacology & Therapeutics, 111(3):707–714, September 2006. URL: http://dx.doi.org/10.1016/j.pharmthera.2005.12.006, doi:10.1016/j.pharmthera.2005.12.006. This article has 74 citations.](https://doi.org/10.1016/j.pharmthera.2005.12.006)

[9. (Pasqualetti1998Distribution) Massimo Pasqualetti, Michela Ori, Irma Nardi, Maura Castagna, Giovanni Batista Cassano, and Donatella Marazziti. Distribution of the 5-ht5a serotonin receptor mrna in the human brain. Molecular Brain Research, 56(1–2):1–8, May 1998. URL: http://dx.doi.org/10.1016/s0169-328x(98)00003-5, doi:10.1016/s0169-328x(98)00003-5. This article has 105 citations.](https://doi.org/10.1016/s0169-328x(98)00003-5)

[10. (Tan2022Structural) Yangxia Tan, Peiyu Xu, Sijie Huang, Gong Yang, Fulai Zhou, Xinheng He, Honglei Ma, H. Eric Xu, and Yi Jiang. Structural insights into the ligand binding and gi coupling of serotonin receptor 5-ht5a. Cell Discovery, May 2022. URL: http://dx.doi.org/10.1038/s41421-022-00412-3, doi:10.1038/s41421-022-00412-3. This article has 15 citations.](https://doi.org/10.1038/s41421-022-00412-3)