Polymorphism in the 5HTR2C Gene – Stress-Induced Cortisol Response
A study published in the journal Biological Psychiatry indicates that functional polymorphism in the 5HTR2C gene may contribute to altered stress reactivity, and to a specific endophenotype that may be linked to an increased risk of cardiovascular disease and type-2 diabetes.
Recent evidence indicates that some psychosocial risk factors such as hostility, depression, social isolation, job stress, and low socioeconomic status may contribute to the etiopathogenesis of cardiovascular disease. In this respect, enhanced hypothalamic-pituitary-adrenal (HPA) axis response to stress is a common mechanism contributing to the psychosocial risk factors’ health-damaging effects. Thus, high levels of hostility have been found to be associated with increased cortisol responses to anger-inducing interpersonal challenge.
Also, increased HPA activation has been implicated in the impact of stress on the pathogenesis of the metabolic syndrome, and elevated cortisol levels appear to mediate the association between depressive symptoms and elevated blood glucose levels. Moreover, glucocorticoid excess and elevated cortisol levels associate with accelerated aging, decreased bone mineral density and increased incident cognitive impairment.
Serotonin acts at multiple sites to contribute to stress-induced HPA axis activation, and signaling through 5HTR2C receptors plays a key role in this process. These sites include the limbic forebrain including the amygdala, where 5-HT stimulates inputs that drive cortocotropin-releasing hormone (CRH) release from the periventricular nucleus (PVN), direct innervation of CRH-containing neurons in the PVN itself by 5-HT through actions on 5-HT2C receptors, and possibly through some peripheral actions directly on the adrenal cortex to stimulate glucocorticoid production.
A single nucleotide polymorphism (SNP) – rs6318; 68G>C – that leads to a substitution of serine for cysteine at codon 23 (Cys23Ser) has been identified, and recent evidence indicates that the Ser23 C allele is constitutively more active than the Cys23 allele.
In the Biological Psychiatry study, Beverly Brummett and colleagues from the Department of Psychiatry, Duke University Medical Center, Durham, NC demonstrate that the cortisol response to a stress task was signiﬁcantly larger in men hemizygous for the Ser23 C allele compared to those carrying the Cys23 G allele.
Men hemizygous for the Ser23 C allele of the 5HT2C rs6318 SNP had both larger cortisol responses and larger increases in anger and depressive mood during the stress protocol. This suggests that the 5HT2C receptor is at least partially responsible for the increase in both HPA axis function and negative moods under stress.
This is also supported by the significant correlations between cortisol increase and the increase in anger during the anger recall task and between cortisol increase and sadness increase during the sadness recall task. That is, in the setting of anger/sadness mood elicitation men with the rs6318 ser23 C allele exhibited larger increases in both HPA axis function and anger/sadness.
Previous research indicates that the Ser23 C variant is also associated with affective disorders, such as major depressive and bipolar disorder. This all together suggests that the rs6318 effects on 5HT2C receptor-mediated effects on both emotions and the HPA axis may be accounting, at least in part, for the linkages between depression and dysregulated HPA axis function.
Moreover, the authors discuss that elevated cortisol levels have been recently associated with a broad range of endophenotypes such as central obesity, elevated glucose, insulin and insulin resistance, higher blood pressure and lipids, as well as diseases – hypertension, coronary heart disease and type-2 diabetes.
Thus, according to the authors the present ﬁndings may also indicate that men carrying the 5HTR2C Ser23 C allele may be more likely than Cys23 G allele carriers to express these endophenotypes.
SOURCE: Biol Psychol 2012, 89:94. Epub 2011 Oct 1.
Cover Image: Left panel: Serotonin 2C receptor gene structure. A) The human full-length 5-HT 2C gene, located on the X chromosome and processed from mRNA encoded from exon 3 to exon 6 after splicing out intronic sequence is depicted (not including 39-or 59-untranslated regions and not according to scale). B) The 5-HT 2C gene is translated into a seven-transmembrane G-protein coupled receptor. The editing cassette is located in the second intracellular loop. C) The nucleotide sequence of the 5-HT 2C editing cassette is depicted including the five nucleotide positions prone to adenosine to inosine editing. doi:10.1371/journal.pone.0032266.g001. From: Dynamic 5-HT2C Receptor Editing in a Mouse Model of Obesity. PLoS ONE 7(3):e32266 DOI:10.1371/journal.pone.0032266; Right panel, Regulation of hypothalamic-pituitary-adrenal (HPA) axis activity: stress as a factor activating the HPA axis. From: HPA Axis in the Pathomechanism of Depression and Schizophrenia: New Therapeutic Strategies Based on Its Participation by Joanna Mikulska et al., Brain Sci. 2021, 11(10), 1298; https://doi.org/10.3390/brainsci11101298