5-HT6 receptor

From Self-sufficiency
Revision as of 20:20, 28 August 2010 by El3ctr0nika (Talk) (Antagonists)

(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)
Jump to: navigation, search
edit
5-hydroxytryptamine (serotonin) receptor 6
Identifiers
SymbolsHTR6; 5-HT6; 5-HT6R
External IDsOMIM601109 MGI1196627 HomoloGene673 IUPHAR: 5-HT6 GeneCards: HTR6 Gene
RNA expression pattern
250px
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez336215565
EnsemblENSG00000158748ENSMUSG00000028747
UniProtP50406Q14AW8
RefSeq (mRNA)NM_000871NM_021358
RefSeq (protein)NP_000862NP_067333
Location (UCSC)Chr 1:
19.86 - 19.88 Mb
Chr 4:
138.33 - 138.35 Mb
PubMed search[1][2]

The 5-HT6 receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5-HT).[1] It is a G protein-coupled receptor (GPCR) that is coupled to Gs/Go and mediates excitatory neurotransmission.[1] HTR6 denotes the human gene encoding for the receptor.[2]

Distribution

The 5-HT6 receptor is expressed almost exclusively in the brain.[3] It is distributed in various areas including, but not limited to, the olfactory tubercle, cerebral cortex (frontal and entorhinal regions), nucleus accumbens, striatum, caudate nucleus, hippocampus, and the molecular layer of the cerebellum.[4][5][1] Based on its abundance in extrapyramidal, limbic, and cortical regions it can be suggested that the 5-HT6 receptor plays a role in functions like motor control, emotionality, cognition, and memory.[5][6][3]

Function

Blockade of central 5-HT6 receptors has been shown to increase glutamatergic and cholinergic neurotransmission in various brain areas,[7][8][9][10] whereas activation enhances GABAergic signaling in a widespread manner.[11] Antagonism of 5-HT6 receptors also facilitates dopamine and norepinephrine release in the frontal cortex,[10][12] while stimulation has the opposite effect.[11]

Despite the 5-HT6 receptor having a functionally excitatory action, it is largely co-localized with GABAergic neurons and therefore produces an overall inhibition of brain activity.[11] In parallel with this, 5-HT6 antagonists improve cognition, learning, and memory,[13] and agents such as latrepirdine, Lu AE58054, and SB-742,457 are being developed as novel treatments for Alzheimer's disease and other dementias.[14][10][15] 5-HT6 antagonists have also been shown to reduce appetite and produce weight loss, and as a result, PRX-07034, BVT-5,182, and BVT-74,316 are being investigated for the treatment of obesity.[16][17]

Recently, the 5-HT6 agonists WAY-181,187 and WAY-208,466 have been demonstrated to be active in rodent models of depression, anxiety, and obsessive-compulsive disorder (OCD), and such agents may be useful treatments for these conditions.[18][11] Additionally, it can be inferred that 5-HT6 activation likely plays a major role in the therapeutic benefits of serotonergic antidepressants like the selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).

Ligands

A large number of selective 5-HT6 ligands have now been developed and this is a productive current area of research.[19][20][21][22][23][24][25]

Full agonists

Partial Agonists

Antagonists

Genetics

The receptor is encoded by the HTR6 gene. As the protein is a neuroreceptor it is possible that genetic variations in the gene would have an effect on brain, and research studies have investigated whether polymorphisms is associated with brain-related variables, such as neuropsychiatric disorders. For example, in 2004 one Chinese study reported an association between the C267T (rs1805054) polymorphism and Alzheimer's disease.[35] Others have studied the polymorphism in relation to Parkinson's disease.[36]

See also

References

Cite error: Invalid <references> tag; parameter "group" is allowed only.

Use <references />, or <references group="..." />

Further reading

External links


This article incorporates text from the United States National Library of Medicine, which is in the public domain.

  1. 1.0 1.1 1.2 Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW (1996). "Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor". J. Neurochem. 66 (1): 47–56. doi:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988. 
  2. "Entrez Gene: HTR6 5-hydroxytryptamine (serotonin) receptor 6". 
  3. 3.0 3.1 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  4. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  5. 5.0 5.1 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  6. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  7. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  8. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  9. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  10. 10.0 10.1 10.2 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  11. 11.0 11.1 11.2 11.3 11.4 11.5 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  12. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  13. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  14. Geldenhuys WJ, Van der Schyf CJ (2008). "Serotonin 5-HT6 receptor antagonists for the treatment of Alzheimer's disease". Current Topics in Medicinal Chemistry. 8 (12): 1035–48. doi:10.2174/156802608785161420. PMID 18691131. 
  15. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  16. 16.0 16.1 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  17. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  18. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  19. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  20. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  21. Lee M, Rangisetty JB, Pullagurla MR; et al. (2005). "1-(1-Naphthyl)piperazine as a novel template for 5-HT6 serotonin receptor ligands". Bioorg. Med. Chem. Lett. 15 (6): 1707–11. doi:10.1016/j.bmcl.2005.01.031. PMID 15745826. 
  22. Sikazwe D, Bondarev ML, Dukat M, Rangisetty JB, Roth BL, Glennon RA (2006). "Binding of sulfonyl-containing arylalkylamines at human 5-HT6 serotonin receptors". J. Med. Chem. 49 (17): 5217–25. doi:10.1021/jm060469q. PMID 16913710. 
  23. Zhou P, Yan Y, Bernotas R; et al. (2005). "4-(2-Aminoethoxy)-N-(phenylsulfonyl)indoles as novel 5-HT6 receptor ligands". Bioorg. Med. Chem. Lett. 15 (5): 1393–6. doi:10.1016/j.bmcl.2005.01.005. PMID 15713394. 
  24. Ahmed M, Briggs MA, Bromidge SM; et al. (2005). "Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists". Bioorg. Med. Chem. Lett. 15 (21): 4867–71. doi:10.1016/j.bmcl.2005.06.107. PMID 16143522. 
  25. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  26. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  27. Glennon RA, Lee M, Rangisetty JB, Dukat M, Roth BL, Savage JE, McBride A, Rauser L, Hufeisen S, Lee DK (2000). "2-Substituted tryptamines: agents with selectivity for 5-HT6 serotonin receptors". J. Med. Chem. 43 (5): 1011–8. doi:10.1021/jm990550b. PMID 10715164. 
  28. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  29. Alcalde E, Mesquida N, López-Pérez S, Frigola J, Mercè R (2009). "Indene-based scaffolds. 2. An indole-indene switch: discovery of novel indenylsulfonamides as 5-HT6 serotonin receptor agonists". J. Med. Chem. 52 (3): 675–87. doi:10.1021/jm8009469. PMID 19159187. 
  30. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  31. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  32. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  33. Wu J, Li Q, Bezprozvanny I. Evaluation of Dimebon in cellular model of Huntington's disease. Molecular Neurodegeneration. 2008 Oct 21;3-15. PMID 18939977
  34. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  35. Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  36. Messina D, Annesi G, Serra P, Nicoletti G, Pasqua A, Annesi F, Tomaino C, Cirò-Candiano IC, Carrideo S, Caracciolo M, Spadafora P, Zappia M, Savettieri G, Quattrone A (12 March 2002). "Association of the 5-HT6 receptor gene polymorphism C267T with Parkinson's disease". Neurology. 58 (5): 828–9. PMID 11889255.