5-HT1A receptor

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5-HT1A
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HTR1A
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000178394

ENSMUSG00000021721

UniProt

P08908

Q64264

RefSeq (mRNA)

NM_000524

NM_008308

RefSeq (protein)

NP_000515

NP_032334

Location (UCSC)Chr 5: 63.96 – 63.96 MbChr 13: 105.58 – 105.58 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The serotonin 1A receptor (or 5-HT1A receptor) is a subtype of

Gi protein, and its activation in the brain mediates hyperpolarization and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A gene.[5][6]

Distribution

The 5-HT1A receptor is the most widespread of all the 5-HT receptors. In the

postsynaptic receptors.[8]

Function

Neuromodulation

5-HT1A

body temperature.[13][14]

Activation of central 5-HT1A receptors triggers the release or inhibition of

Edinger-Westphal nucleus, resulting in pupil dilation in rodents, and pupil constriction in primates including humans.[15][16][17]

5-HT1A receptor agonists like buspirone[18] and flesinoxan[19] show efficacy in relieving anxiety[20] and depression.[21] Buspirone and tandospirone are currently approved for these indications in different parts of the world. Others such as gepirone,[22] flesinoxan,[19] flibanserin,[23] and naluzotan[24] have also been investigated, though none have been fully developed and approved yet. Some of the atypical antipsychotics like lurasidone[25] and aripiprazole[26] are also partial agonists at the 5-HT1A receptor and are sometimes used in low doses as augmentations to standard antidepressants like the selective serotonin reuptake inhibitors (SSRIs).[27] Mice lacking 5-HT1A receptors altogether (knockout) show increased anxiety but lower depressive-like behaviour.[28]

5-HT1A autoreceptor desensitization and increased 5-HT1A receptor postsynaptic activation via general increases in serotonin levels by serotonin

releasing agents (SRAs) like MDMA (commonly known as ecstasy) as well.[30][31]

5-HT1A receptors in the

emesis, and are also being investigated for the treatment of anxiety and depression.[38]

5-HT1A receptor activation has been shown to increase

medial prefrontal cortex, striatum, and hippocampus, and may be useful for improving the symptoms of schizophrenia and Parkinson's disease.[39] As mentioned above, some of the atypical antipsychotics are 5-HT1A receptor partial agonists, and this property has been shown to enhance their clinical efficacy.[39][40][41] Enhancement of dopamine release in these areas may also play a major role in the antidepressant and anxiolytic effects as seen upon postsynaptic activation of the 5-HT1A receptor.[42][43]

The activation of 5-HT1A receptors has been demonstrated to impair certain aspects of

glutamate blockade (with dizocilpine)[46] or hippocampal cholinergic denervation (by fornix transection)[47] in primates. Furthermore, 5-HT1A receptor antagonists such as lecozotan have been shown to facilitate certain types of learning and memory in rodents, and as a result, are being developed as novel treatments for Alzheimer's disease.[48]

Other effects of 5-HT1A activation that have been observed in scientific research include:

Endocrinology

5-HT1A receptor activation induces the

β-endorphin.[63][64][65][66] The receptor does not affect vasopressin or renin secretion, unlike the 5-HT2 receptors.[63][64] It has been suggested that oxytocin release may contribute to the prosocial, antiaggressive, and anxiolytic properties observed upon activation of the receptor.[31] β-Endorphin secretion may contribute to antidepressant, anxiolytic, and analgesic effects.[67]

Autoreceptors

5-HT1A receptors can be located on the

somatodendritic, and those located presynaptically in the synapse are simply referred to as presynaptic. As a group, receptors that are sensitive to the neurotransmitter that is released by the neuron on which the receptors are located are known as autoreceptors
; they typically constitute the key component of an ultra-short negative feedback loop whereby the neuron's release of neurotransmitter inhibits its further release of neurotransmitter. Stimulation of 5-HT1A autoreceptors inhibits the release of serotonin in nerve terminals. For this reason, 5-HT1A receptor agonists tend to exert a biphasic mode of action; they decrease serotonin release and postsynaptic 5-HT1A receptor activity in low doses, and further decrease serotonin release but increase postsynaptic 5-HT1A receptor activity at higher doses by directly stimulating the receptors in place of serotonin.

This autoreceptor-mediated inhibition of serotonin release has been theorized to be a major factor in the therapeutic lag that is seen with serotonergic antidepressants such as the SSRIs.

desensitize before the concentration of extracellular serotonin in the synapse can become elevated appreciably.[68][69] Though the responsiveness of the autoreceptors is somewhat reduced with chronic treatment, they still remain effective at constraining large increases in extracellular serotonin concentrations.[68] For this reason, serotonin reuptake inhibitors that also have 5-HT1A receptor antagonistic or partial agonistic properties, such as vilazodone and SB-649,915, are being investigated and introduced as novel antidepressants with the potential for a faster onset of action and improved effectiveness compared to those currently available.[70]

Unlike most drugs that elevate extracellular serotonin levels like the SSRIs and MAOIs, SRAs such as

selective serotonin releasing agents (SSRAs) such as MDAI and MMAI have been proposed as novel antidepressants with a putatively faster onset of action and improved effectiveness compared to current treatments.[72]

Similarly to SRAs, sufficiently high doses of 5-HT1A receptor agonists also bypass the 5-HT1A autoreceptor-mediated inhibition of serotonin release and therefore increase 5-HT1A postsynaptic receptor activation by directly agonizing the postsynaptic receptors

in lieu
of serotonin.

Ligands

The distribution of 5-HT1A receptors in the

WAY-100,635.[77]
For example, one study has found increased 5-HT1A binding in type 2
autoradiography.[80]

Agonists

Partial agonists

Full agonists

Biased agonists

Antagonists

[92]

Allosteric Modulators

Genetics

The 5-HT1A receptor is coded by the HTR1A

psychiatric disorders with no definitive results.[97]

Protein-protein interactions

The 5-HT1A receptor has been shown to

interact with brain-derived neurotrophic factor (BDNF), which may play a major role in its regulation of mood and anxiety.[99][100]

Receptor oligomers

The 5-HT1A receptor forms

5-HT1D, GABAB2, LPA1 (GPCR26), LPA3, S1P1, S1P3.[102]

See also

References

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External links

Wikimedia Commons has media related to 5-HT1A serotonin receptor.
  • "5-HT1A". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2012-09-02. Retrieved 2008-11-24.
  • Human HTR1A genome location and HTR1A gene details page in the UCSC Genome Browser.

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

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