Biology:5-HT7 receptor

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


The 5-HT7 receptor is a member of the GPCR superfamily of cell surface receptors and is activated by the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT)[1] The 5-HT7 receptor is coupled to Gs (stimulates the production of the intracellular signaling molecule cAMP)[2][3] and is expressed in a variety of human tissues, particularly in the brain, the gastrointestinal tract, and in various blood vessels.[3] This receptor has been a drug development target for the treatment of several clinical disorders.[4] The 5-HT7 receptor is encoded by the HTR7 gene, which in humans is transcribed into 3 different splice variants.[5]

Function

When the 5-HT7 receptor is activated by serotonin, it sets off a cascade of events starting with release of the stimulatory G protein Gs from the GPCR complex. Gs in turn activates adenylate cyclase which increases intracellular levels of the second messenger cAMP.

The 5-HT7 receptor plays a role in smooth muscle relaxation within the vasculature and in the gastrointestinal tract.[1] The highest 5-HT7 receptor densities are in the thalamus and hypothalamus, and it is present at higher densities also in the hippocampus and cortex. The 5-HT7 receptor is involved in thermoregulation, circadian rhythm, learning and memory, and sleep. Peripheral 5-HT7 receptors are localized in enteric nerves; high levels of 5-HT7 receptor-expressing mucosal nerve fibers were observed in the colon of patients with irritable bowel syndrome. An essential role of 5-HT7 receptor in intestinal hyperalgesia was demonstrated in mouse models with visceral hypersensitivity, of which a novel 5-HT7 receptor antagonist administered perorally reduced intestinal pain levels.[6] It is also speculated that this receptor may be involved in mood regulation, suggesting that it may be a useful target in the treatment of depression.[7][8]

Variants

Three splice variants have been identified in humans (designated h5-HT7(a), h5-HT7(b), and h5-HT7(d)), which encode receptors that differ in their carboxy terminals.[5] The h5-HT7(a) is the full length receptor (445 amino acids),[3] while the h5-HT7(b) is truncated at amino acid 432 due to alternative splice donor site. The h5-HT7(d) is a distinct isoform of the receptor: the retention of an exon cassette in the region encoding the carboxyl terminal results a 479-amino acid receptor with a c-terminus markedly different from the h5-HT7(a). A 5-HT7(c) splice variant is detectable in rat tissue but is not expressed in humans. Conversely, rats do not express a splice variant homologous to the h5-HT7(d), as the rat 5-HT7 gene lacks the exon necessary to encode this isoform.[5] Drug binding affinities are similar across the three human splice variants;[9] however, inverse agonist efficacies appear to differ between the splice variants.[10]

Discovery

In 1983, evidence for a 5-HT1-like receptor was first found.[11] Ten years later, 5-HT7 receptor was cloned and characterized.[3] It has since become clear that the receptor described in 1983 is 5-HT7.[12]

Ligands

Numerous orthosteric ligands of moderate to high affinity are known. Signaling biased ligands were discovered and developed in 2018.[13]

Agonists

Agonists mimic the effects of the endogenous ligand, which is serotonin at the 5-HT7 receptor (↑cAMP).


Antagonists

Neutral antagonists (also known as silent antagonists) bind the receptor and have no intrinsic activity but will block the activity of agonists or inverse agonists. Inverse agonists inhibit the constitutive activity of the receptor, producing functional effects opposite to those of agonists (at the 5-HT7 receptor: ↓cAMP).[25][26] Neutral antagonists and inverse agonists are typically referred to collectively as "antagonists" and, in the case of the 5-HT7 receptor, differentiation between neutral antagonists and inverse agonists is problematic due to differing levels of inverse agonist efficacy between receptor splice variants. For instance, mesulergine and metergoline are reported to be neutral antagonists at the h5-HT7(a) and h5-HT7(d) receptor isoforms but these drugs display marked inverse agonist effects at the h5-HT7(b) splice variant.[10]



Inactivating antagonists

Inactivating antagonists are non-competitive antagonists that render the receptor persistently insensitive to agonist, which resembles receptor desensitization. Inactivation of the 5-HT7 receptor, however, does not arise from the classically described mechanisms of receptor desensitization via receptor phosphorylation, beta-arrestin recruitment, and receptor internalization.[36] Inactivating antagonists all likely interact with the 5-HT7 receptor in an irreversible/pseudo-irreversible manner, as is the case with [3H]risperidone.[37][38]


See also


References

  1. ↑ 1.0 1.1 "5-HT7 receptors: current knowledge and future prospects". Trends in Pharmacological Sciences 21 (2): 70–7. February 2000. doi:10.1016/S0165-6147(99)01432-7. PMID 10664612. 
  2. ↑ "Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation". Proceedings of the National Academy of Sciences of the United States of America 90 (18): 8547–51. September 1993. doi:10.1073/pnas.90.18.8547. PMID 8397408. Bibcode: 1993PNAS...90.8547R. 
  3. ↑ 3.0 3.1 3.2 3.3 "Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase". The Journal of Biological Chemistry 268 (31): 23422–6. November 1993. doi:10.1016/S0021-9258(19)49479-9. PMID 8226867. 
  4. ↑ "5-HT7 receptor antagonists as a new class of antidepressants". Drug News & Perspectives 20 (10): 613–8. December 2007. doi:10.1358/dnp.2007.20.10.1181354. PMID 18301795. 
  5. ↑ 5.0 5.1 5.2 "Four 5-hydroxytryptamine7 (5-HT7) receptor isoforms in human and rat produced by alternative splicing: species differences due to altered intron-exon organization". Journal of Neurochemistry 68 (4): 1372–81. April 1997. doi:10.1046/j.1471-4159.1997.68041372.x. PMID 9084407. 
  6. ↑ 6.0 6.1 "5-HT 7 receptor-dependent intestinal neurite outgrowth contributes to visceral hypersensitivity in irritable bowel syndrome". Laboratory Investigation 102 (9): 1023–1037. 2022. doi:10.1038/s41374-022-00800-z. PMID 35585132. 
  7. ↑ "Functional, molecular and pharmacological advances in 5-HT7 receptor research". Trends in Pharmacological Sciences 25 (9): 481–6. September 2004. doi:10.1016/j.tips.2004.07.002. PMID 15559250. 
  8. ↑ "Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders". CNS Neuroscience & Therapeutics 20 (7): 582–90. July 2014. doi:10.1111/cns.12247. PMID 24935787. 
  9. ↑ "The cloned human 5-HT7 receptor splice variants: a comparative characterization of their pharmacology, function and distribution". Naunyn-Schmiedeberg's Archives of Pharmacology 363 (6): 620–32. June 2001. doi:10.1007/s002100000369. PMID 11414657. 
  10. ↑ 10.0 10.1 "The human 5-HT7 serotonin receptor splice variants: constitutive activity and inverse agonist effects". British Journal of Pharmacology 135 (6): 1563–71. March 2002. doi:10.1038/sj.bjp.0704588. PMID 11906971. 
  11. ↑ "5-Hydroxytryptamine-induced relaxation of isolated mammalian smooth muscle". European Journal of Pharmacology 96 (1–2): 71–8. December 1983. doi:10.1016/0014-2999(83)90530-7. PMID 6662198. 
  12. ↑ "Molecular, pharmacological and functional diversity of 5-HT receptors". Pharmacology Biochemistry and Behavior 71 (4): 533–54. April 2002. doi:10.1016/S0091-3057(01)00746-8. PMID 11888546. 
  13. ↑ "Discovery of β-Arrestin Biased Ligands of 5-HT7R". J. Med. Chem. 61 (16): 7218–7233. August 2018. doi:10.1021/acs.jmedchem.8b00642. PMID 30028132. 
  14. ↑ "8-OH-DPAT as a 5-HT7 agonist: phase shifts of the circadian biological clock through increases in cAMP production". Neuropharmacology 46 (1): 52–62. January 2004. doi:10.1016/j.neuropharm.2003.08.007. PMID 14654097. 
  15. ↑ Davies MA, Sheffler DJ, Roth BL. Aripiprazole: A Novel Atypical Antipsychotic Drug With a Uniquely Robust Pharmacology. CNS Drug Reviews [Internet]. 2004 [cited 2013 Aug 4];10(4):317–36. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2004.tb00030.x/pdf
  16. ↑ "Potentiation of morphine analgesia by adjuvant activation of 5-HT7 receptors". Journal of Pharmacological Sciences 116 (4): 388–91. August 2011. doi:10.1254/jphs.11039sc. PMID 21778664. 
  17. ↑ "Pharmacological activation of 5-HT7 receptors reduces nerve injury-induced mechanical and thermal hypersensitivity". Pain 149 (3): 483–94. June 2010. doi:10.1016/j.pain.2010.03.007. PMID 20399562. 
  18. ↑ "5-HT7 receptor activation inhibits mechanical hypersensitivity secondary to capsaicin sensitization in mice". Pain 141 (3): 239–47. February 2009. doi:10.1016/j.pain.2008.11.009. PMID 19118950. 
  19. ↑ "In vitro serotonergic activity of black cohosh and identification of N(omega)-methylserotonin as a potential active constituent". Journal of Agricultural and Food Chemistry 56 (24): 11718–26. December 2008. doi:10.1021/jf803298z. PMID 19049296. 
  20. ↑ "Structure-activity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides, a class of 5-HT7 receptor agents. 2". Journal of Medicinal Chemistry 50 (17): 4214–21. August 2007. doi:10.1021/jm070487n. PMID 17649988. 
  21. ↑ "Structure-affinity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides, a new class of 5-hydroxytryptamine7 receptor agents". Journal of Medicinal Chemistry 47 (26): 6616–24. December 2004. doi:10.1021/jm049702f. PMID 15588097. 
  22. ↑ "Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol". Scientific Reports 7 (1444): 1444. May 2017. doi:10.1038/s41598-017-00822-4. PMID 28473721. Bibcode: 2017NatSR...7.1444H. 
  23. ↑ "Search for a 5-CT alternative. In vitro and in vivo evaluation of novel pharmacological tools: 3-(1-alkyl-1H-imidazol-5-yl)-1H-indole-5-carboxamides, low-basicity 5-HT7 receptor agonists.". MedChemComm 9 (11): 1882–1890. September 2018. doi:10.1039/c8md00313k. PMID 30568756. 
  24. ↑ "Fluorinated indole-imidazole conjugates: Selective orally bioavailable 5-HT7 receptor low-basicity agonists, potential neuropathic painkillers". European Journal of Medicinal Chemistry 170: 261–275. 2019. doi:10.1016/j.ejmech.2019.03.017. PMID 30904783. 
  25. ↑ "5-HT7 receptor ligands: recent developments and potential therapeutic applications". Mini Reviews in Medicinal Chemistry 7 (9): 945–60. September 2007. doi:10.2174/138955707781662663. PMID 17897083. 
  26. ↑ "Serotonin(7) receptors (5-HT(7)Rs) and their ligands". Current Medicinal Chemistry 11 (5): 629–61. March 2004. doi:10.2174/0929867043455828. PMID 15032609. 
  27. ↑ "(Phenylpiperazinyl-butyl)oxindoles as selective 5-HT7 receptor antagonists". Journal of Medicinal Chemistry 51 (8): 2522–32. April 2008. doi:10.1021/jm070279v. PMID 18361484. 
  28. ↑ "Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo". Psychopharmacology 205 (1): 119–28. July 2009. doi:10.1007/s00213-009-1521-8. PMID 19337725. 
  29. ↑ "AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders.". J. Alzheimer's Dis. 53 (2): 583–620. 2016. doi:10.3233/JAD-151146. PMID 27232215. 
  30. ↑ "Investigations on the 1-(2-Biphenyl)piperazine Motif: Identification of New Potent and Selective Ligands for the Serotonin7 (5-HT7) Receptor with Agonist or Antagonist Action in Vitro or ex Vivo". Journal of Medicinal Chemistry 55 (14): 6375–6380. 2012. doi:10.1021/jm3003679. PMID 22738316. 
  31. ↑ 31.0 31.1 "Reanalysis of constitutively active rat and human 5-HT7(a) receptors in HEK-293F cells demonstrates lack of silent properties for reported neutral antagonists". Naunyn-Schmiedeberg's Archives of Pharmacology 374 (1): 31–9. October 2006. doi:10.1007/s00210-006-0093-y. PMID 16967291. 
  32. ↑ "(R)-3,N-dimethyl-N-[1-methyl-3-(4-methyl-piperidin-1-yl) propyl]benzenesulfonamide: the first selective 5-HT7 receptor antagonist". Journal of Medicinal Chemistry 41 (5): 655–7. February 1998. doi:10.1021/jm970519e. PMID 9513592. 
  33. ↑ 33.0 33.1 "Differential inverse agonist efficacies of SB-258719, SB-258741 and SB-269970 at human recombinant serotonin 5-HT7 receptors". European Journal of Pharmacology 495 (2–3): 97–102. July 2004. doi:10.1016/j.ejphar.2004.05.033. PMID 15249157. 
  34. ↑ "A novel, potent, and selective 5-HT(7) antagonist: (R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulfonyl) phen ol (SB-269970)". Journal of Medicinal Chemistry 43 (3): 342–5. February 2000. doi:10.1021/jm991151j. PMID 10669560. 
  35. ↑ "SB-656104-A: a novel 5-HT(7) receptor antagonist with improved in vivo properties". Bioorganic & Medicinal Chemistry Letters 12 (22): 3341–4. November 2002. doi:10.1016/S0960-894X(02)00690-X. PMID 12392747. 
  36. ↑ "Molecular mechanisms of G protein-coupled receptor signaling: role of G protein-coupled receptor kinases and arrestins in receptor desensitization and resensitization". Receptors & Channels 5 (3–4): 193–9. 1997. PMID 9606723. 
  37. ↑ 37.0 37.1 37.2 37.3 "Risperidone irreversibly binds to and inactivates the h5-HT7 serotonin receptor". Molecular Pharmacology 70 (4): 1264–70. October 2006. doi:10.1124/mol.106.024612. PMID 16870886. 
  38. ↑ 38.0 38.1 38.2 38.3 "Pharmacological analysis of the novel, rapid, and potent inactivation of the human 5-Hydroxytryptamine7 receptor by risperidone, 9-OH-Risperidone, and other inactivating antagonists". Molecular Pharmacology 75 (2): 374–80. February 2009. doi:10.1124/mol.108.052084. PMID 18996971. 

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