Alternative titles; symbols
HGNC Approved Gene Symbol: HTR1A
SNOMEDCT: 1169366007;
Cytogenetic location: 5q12.3 Genomic coordinates (GRCh38): 5:63,957,874-63,962,445 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q12.3 | Periodic fever, menstrual cycle dependent | 614674 | Autosomal dominant | 3 |
Kobilka et al. (1987) cloned and sequenced a DNA fragment in the human genome which cross-hybridizes with a full-length beta-2-adrenergic receptor at reduced stringency. Like the beta-2-adrenergic receptor (109690), this gene appears to be intronless, containing an uninterrupted long open reading frame which encodes a putative protein with all the expected structural features of a G protein-coupled receptor. Although the G-21 clone was found to map to the same location as that for the glucocorticoid receptor (138040) (see later), Kobilka et al. (1987) thought it unlikely that G-21 represents a pseudogene for the beta-2-adrenergic receptor or some other gene for several reasons. Most pseudogenes do not contain uninterrupted coding blocks because of the lack of selected pressure in preventing termination mutations. For the same reason one would not expect to find well-conserved regions of homology such as those observed between the G-21 and the G protein-coupled receptors. Finally, the G-21 gene is expressed in several tissues as revealed by Northern blot analysis. The tissue distribution of the mRNA is unique, being highest in lymphoid tissues.
Kobilka et al. (1987) determined the chromosomal localization of the G-21 clone (the designation for the DNA segment) by Southern blot analysis of DNA from 12 hamster and human somatic cell hybrids and by in situ hybridization. By these methods it was found to be located at 5q11.2-q13. Melmer et al. (1991) showed close linkage of HTR1A to highly polymorphic microsatellite markers on chromosome 5. Oakey et al. (1991) mapped the Htra1 gene to distal mouse chromosome 13.
Fargin et al. (1988) reported that the protein product of the genomic clone G21, transiently expressed in monkey kidney cells, has all the typical ligand-binding characteristics of the 5-hydroxytryptamine (5-HT-1A) receptor. At least 6 subtypes of 5-HT receptors (1A, 1B, 1C, 1D, 2, and 3) have been characterized extensively by pharmacologic and physiologic methods. See review by El Mestikawy et al. (1991).
Various chronic antidepressant treatments increase adult hippocampal neurogenesis. Santarelli et al. (2003) used genetic and radiologic methods to show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor-null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin-selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of 2 classes of antidepressants, SSRIs and tricyclics. Santarelli et al. (2003) concluded that their findings suggested that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.
Using a selective molecular probe and PET scan, Kepe et al. (2006) found decreased density of 5-HT-1A receptors in the hippocampus of 8 patients with Alzheimer disease (AD; 104300) and 6 patients with mild cognitive impairment compared to 5 normal controls. The decreases in 5-HT-1A receptor densities correlated with decreased glucose utilization as measured by PET scan.
In a 33-year-old Taiwanese woman with menstrual cycle-dependent periodic fevers (614674) that were successfully treated with a serotonin receptor antagonist, Jiang et al. (2012) identified a 1-bp deletion in the upstream promoter (109760.0001). Functional analysis demonstrated that the mutant promoter has increased interaction with a negative regulator of HTR1A expression, PARP1 (173870), and causes additional reduction in transcription.
Brain serotonin has been implicated in a number of physiologic processes and pathologic conditions. These effects are mediated by at least 14 different 5-HT receptors. Parks et al. (1998) inactivated the gene encoding the 5-HT-1A receptor in mice and found that receptor-deficient animals had an increased tendency to avoid a novel and fearful environment and to escape a stressful situation, behaviors consistent with an increased anxiety and stress response. Based on the role of the 5-HT-1A receptor and the feedback regulation of the 5-HT system, Parks et al. (1998) hypothesized that an increased serotonergic neurotransmission is responsible for the anxiety-like behavior of receptor-deficient animals. This view is consistent with earlier studies showing that pharmacologic activation of the 5-HT system is anxiogenic in animal models and also in humans.
To investigate the contribution of individual serotonin receptors to mood control, homologous recombination to generate mice lacking specific serotonergic receptor subtypes has been used. Ramboz et al. (1998) demonstrated that mice without 5-HT-1A receptors displayed decreased exploratory activity and increased fear of aversive environments (open or elevated spaces). 5-HT-1A knockout mice also exhibited a decreased immobility in the forced swim test, an effect commonly associated with antidepressant treatment. Although 5-HT-1A receptors are involved in controlling the activity of serotonergic neurons, these knockout mice had normal levels of 5-HT and 5-hydroxyindoleacetic acid, possibly because of an upregulation of 5-HT-1B autoreceptors. Heterozygous 5-HT-1A mutants expressed approximately one-half of wildtype receptor density and displayed intermediate phenotypes in most behavioral tests. These results demonstrated that 5-HT-1A receptors are involved in the modulation of exploratory and fear-related behaviors and suggested that reductions in 5-HT-1A receptor density due to genetic defects are environmental stressors that may result in heightened anxiety.
Heisler et al. (1998) used a gene-targeting technology to generate mice deficient in 5-HT-1A receptors. Homozygous mutants displayed a consistent pattern of responses indicative of elevated anxiety levels in open-field, elevated-zero maze, and novel-object assays. Moreover, they exhibited antidepressant-like responses in a tail-suspension assay. These results were interpreted as indicating that the targeted disruption of the serotonin receptor gene leads to heritable perturbations in the serotonergic regulation of emotional state. Although some of the behavioral assays differed in design and the mouse lines used differed in their genetic backgrounds, the results of Ramboz et al. (1998) and Heisler et al. (1998) led to essentially the same conclusions. In each case, homozygous mutant mice showed less exploratory behavior than wildtype mice. Whatever the mechanism, these studies provided another example of how a single gene mutation can alter behavior. Julius (1998) suggested that 'the most significant question may be whether behavioral changes in these mice will be good predictors of anxiolytic drug activity in humans. If so, then 5-HT-1A receptor knockout mice may earn their keep as sentinels for new therapeutic compounds.'
Gross et al. (2002) used a tissue-specific, conditional rescue strategy to show that expression of the serotonin-1A receptor primarily in the hippocampus and cortex, but not in the raphe nuclei, is sufficient to rescue the behavioral phenotype of knockout mice. Furthermore, using the conditional nature of the transgenic mice, Gross et al. (2002) suggested that receptor expression during the early postnatal period, but not in the adult, is necessary for this behavioral rescue. Gross et al. (2002) concluded that postnatal developmental processes help to establish adult anxiety-like behavior. In addition, the normal role of the serotonin-1A receptor during development may be different from its function when this receptor is activated by therapeutic intervention in adulthood.
Audero et al. (2008) investigated the consequences of altering the autoinhibitory capacity of serotonin neurons with the reversible overexpression of serotonin-1A autoreceptors in transgenic mice. Overexpressing mice exhibited sporadic bradycardia and hypothermia that occurred during a limited developmental period and frequently progressed to death. Moreover, overexpressing mice failed to activate autonomic target organs in response to environmental challenges. Audero et al. (2008) concluded that their findings showed that excessive serotonin autoinhibition is a risk factor for catastrophic autonomic dysregulation and provided a mechanism for a role of altered serotonin homeostasis in sudden infant death syndrome (SIDS; 272120).
Richardson-Jones et al. (2010) generated transgenic mice with decreased levels of serotonin-1A autoreceptors in the raphe nuclei but no change in serotonin-1A heteroreceptors. Mice with low 5HT1A autoreceptor levels had increased spontaneous activity of serotonergic neurons compared to mice with high 5HT1A levels, consistent with decreased autoinhibition in the former group. Compared to mice with high 5HT1A autoreceptor levels, mice with low 5HT1A autoreceptor levels had an increased physiologic response to acute stress, decreased behavioral despair, and better behavioral response to the antidepressant fluoxetine. After 8 days of fluoxetine treatment, low 5HT1A mice had increased serotonin levels in the hippocampus compared to high 5HT1A mice, although levels in both mice increased and were normalized by 26 days. A reduction in 5HT1A autoreceptor levels prior to antidepressant treatment resulted in better response to treatment, suggesting that decreased autoreceptor function may allow an earlier response to treatment. The findings were consistent with the hypothesis that feedback inhibition by 5HT1A autoreceptors delays onset of response by limiting the initial increase in serotonin. Although 5HT1A autoreceptors desensitized after chronic treatment with fluoxetine, desensitization alone was not sufficient to explain the response to fluoxetine. Serotonergic tone, governed by intrinsic autoreceptor levels, prior to the onset of treatment appeared to be critical for establishing responsiveness. The results established a causal relationship between 5HT1A autoreceptor levels, resilience under stress, and response to antidepressants.
In a 33-year-old Taiwanese woman with menstrual cycle-dependent periodic fevers (614674), Jiang et al. (2012) identified heterozygosity for a 1-bp deletion 480 bases upstream of the HTR1A translation start site (-480delA). The mutation was also identified in her father and brother, who had serotonin-related disorders such as diabetes and migraines, but was not found in her unaffected mother or sister or in 50 unrelated population controls. Functional analysis demonstrated that HTR1A can be bound by multiple nuclear proteins, including PARP1 (173870), and PARP1 was shown to repress HTR1A transcription. In addition, mutant (-480delA) HTR1A was shown to possess increased interaction with PARP1, causing an additional reduction in transcription, and administration of 17-beta-estradiol further reduced transcription associated with the mutant promoter. Jiang et al. (2012) suggested that estrogen-induced hyperactivity of the HRT1A mutant promoter causes the reduction of HTR1A mRNA and leads to the disruption of HTR1A-mediated thermoregulation.
Audero, E., Coppi, E., Mlinar, B., Rossetti, T., Caprioli, A., Banchaabouchi, M. A., Corradetti, R., Gross, C. Sporadic autonomic dysregulation and death associated with excessive serotonin autoinhibition. Science 321: 130-133, 2008. [PubMed: 18599790] [Full Text: https://doi.org/10.1126/science.1157871]
El Mestikawy, S., Fargin, A., Raymond, J. R., Gozlan, H., Hnatowich, M. The 5-HT(1A) receptor: an overview of recent advances. Neurochem. Res. 16: 1-10, 1991. [PubMed: 2052135] [Full Text: https://doi.org/10.1007/BF00965820]
Fargin, A., Raymond, J. R., Lohse, M. J., Kobilka, B. K., Caron, M. G., Lefkowitz, R. J. The genomic clone G-21 which resembles a beta-adrenergic receptor sequence encodes the 5-HT(1A) receptor. Nature 335: 358-360, 1988. [PubMed: 3138543] [Full Text: https://doi.org/10.1038/335358a0]
Gross, C., Zhuang, X., Stark, K., Ramboz, S., Oosting, R., Kirby, L., Santarelli, L., Beck, S., Hen, R. Serotonin-1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416: 396-400, 2002. [PubMed: 11919622] [Full Text: https://doi.org/10.1038/416396a]
Heisler, L. K., Chu, H.-M., Brennan, T. J., Danao, J. A., Bajwa, P., Parsons, L. H., Tecott, L. H. Elevated anxiety and antidepressant-like responses in serotonin 5-HT(1A) receptor mutant mice. Proc. Nat. Acad. Sci. 95: 15049-15054, 1998. [PubMed: 9844013] [Full Text: https://doi.org/10.1073/pnas.95.25.15049]
Jiang, Y.-C., Wu, H.-M., Cheng, K.-H., Sunny Sun, H. Menstrual cycle-dependent febrile episode mediated by sequence-specific repression of poly(ADP-ribose) polymerase-1 on the transcription of the human serotonin receptor 1A gene. Hum. Mutat. 33: 209-217, 2012. [PubMed: 21990073] [Full Text: https://doi.org/10.1002/humu.21622]
Julius, D. Serotonin receptor knockouts: a moody subject. Proc. Nat. Acad. Sci. 95: 15153-15154, 1998. [PubMed: 9860934] [Full Text: https://doi.org/10.1073/pnas.95.26.15153]
Kepe, V., Barrio, J. R., Huang, S.-C., Ercoli, L., Siddarth, P., Shoghi-Jadid, K., Cole, G. M., Satyamurthy, N., Cummings, J. L., Small, G. W., Phelps, M. E. Serotonin 1A receptors in the living brain of Alzheimer's disease patients. Proc. Nat. Acad. Sci. 103: 702-707, 2006. [PubMed: 16407119] [Full Text: https://doi.org/10.1073/pnas.0510237103]
Kobilka, B. K., Frielle, T., Collins, S., Yang-Feng, T., Kobilka, T. S., Francke, U., Lefkowitz, R. J., Caron, M. G. An intronless gene encoding a potential member of the family of receptors coupled to guanine nucleotide regulatory proteins. Nature 329: 75-79, 1987. [PubMed: 3041227] [Full Text: https://doi.org/10.1038/329075a0]
Melmer, G., Sherrington, R., Mankoo, B., Kalsi, G., Curtis, D., Gurling, H. M. D. A cosmid clone for the 5HT1A receptor (HTR1A) reveals a TaqI RFLP that shows tight linkage to DNA loci D5S6, D5S39, and D5S76. Genomics 11: 767-769, 1991. [PubMed: 1685484] [Full Text: https://doi.org/10.1016/0888-7543(91)90088-v]
Oakey, R. J., Caron, M. G., Lefkowitz, R. J., Seldin, M. F. Genomic organization of adrenergic and serotonin receptors in the mouse: linkage mapping of sequence-related genes provides a method for examining mammalian chromosome evolution. Genomics 10: 338-344, 1991. [PubMed: 1676978] [Full Text: https://doi.org/10.1016/0888-7543(91)90317-8]
Parks, C. L., Robinson, P. S., Sibille, E., Shenk, T., Toth, M. Increased anxiety of mice lacking the serotonin-1A receptor. Proc. Nat. Acad. Sci. 95: 10734-10739, 1998. [PubMed: 9724773] [Full Text: https://doi.org/10.1073/pnas.95.18.10734]
Ramboz, S., Oosting, R., Amara, D. A., Kung, H. F., Blier, P., Mendelsohn, M., Mann, J. J., Brunner, D., Hen, R. Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. Proc. Nat. Acad. Sci. 95: 14476-14481, 1998. [PubMed: 9826725] [Full Text: https://doi.org/10.1073/pnas.95.24.14476]
Richardson-Jones, J. W., Craige, C. P., Guiard, B. P., Stephen, A., Metzger, K. L., Kung, H. F., Gardier, A. M., Dranovsky, A., David, D. J., Beck, S. G., Hen, R., Leonardo, E. D. 5-HT-1A autoreceptor levels determine vulnerability to stress and response to antidepressants. Neuron 65: 40-52, 2010. [PubMed: 20152112] [Full Text: https://doi.org/10.1016/j.neuron.2009.12.003]
Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., Weisstaub, N., Lee, J., Duman, R., Arancio, O., Belzung, C., Hen, R. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301: 805-809, 2003. [PubMed: 12907793] [Full Text: https://doi.org/10.1126/science.1083328]