Expression of corticotropin releasing hormone receptors type I and type II mRNA in suicide victims and controls

Abstract

Corticotropin-releasing hormone (CRH) is a key neuroendocrine factor implementing endocrine, immune and behavioral responses to stress. CRH exerts its action through two major receptors, CRH-R1 and CRH-R2. Recently novel non-peptidic antagonists directed against CRH-R1 or CRH-R2 have been proposed as promising agents in the treatment of depression, anxiety and eating disorder. However, so far the CRH-receptor system has not been widely studied in humans. Therefore, we employed quantitative TaqMan PCR to analyze the expression and distribution of both CRH-R1 and CRH-R2 in human brain tissue and peripheral organs. Furthermore the expression of CRH receptors was analyzed for the first time in pituitaries of suicide victims by in situ hybridization and quantitative PCR. Our data demonstrated a different expression pattern in humans as compared to rodents. Both CRH-R1 and CRH-R2 were expressed in high amounts in the brain with the strongest expression in the pituitary. As described in rodents, however the CRH-R1 in human was the predominant receptor in the brain (82.7 ± 11.0%), whilst CRH-R2 was the predominant receptor in peripheral organs (77.0 ± 15.8%). There was a shift in the ratio of CRH-R1/R2 in the pituitaries of suicide victims. In conclusion, both CRH-R1 and CRH-R2 are widely expressed in human tissues with a distribution substantially different from rodents. Strong expression of both CRH-R1 and CRH-R2 in human pituitaries suggests that particularly under stress, activation of the HPA axis can be maintained through both receptors. Molecular Psychiatry (2001) 6, 540-546.

High-Affinity CRF1 Receptor Antagonist NBI-34041: Preclinical and Clinical Data Suggest Safety and Efficacy in Attenuating Elevated Stress Response

“…As CRF 1 receptors are more abundantly expressed in the anterior pituitary than in the cortex (Hiroi et al, 2001;Sanchez et al, 1999), moderate to high doses of CRF 1 antagonists exhibit a sufficient blockade of CRF 1 receptors in the prefrontal cortex and the amygdala, but not in the pituitary. This is also supported by the divergent effects of subchronic NBI-34041 treatment in our clinical study; although HPA responsiveness following direct stimulation of the anterior pituitary by exogenous CRF was preserved, the HPA response to psychosocial stressor was attenuated.…”

“…These receptors have been termed the CRF 1 and the CRF 2 receptor with the CRF 2 receptor existing in three identified splice variant isoforms named CRF 2(a) , CRF 2(b), and CRF 2(c) (Hauger et al, 2003). Both receptor subtypes are found in human pituitary (Hiroi et al, 2001) and throughout the neocortex of primates (Sanchez et al, 1999), whereas in rodents only the CRF 1 receptor is expressed in pituitary and neocortex, and has a discrete localization with respect to the CRF 2 receptor (Chalmers et al, 1995). In addition to the neuropeptide CRF itself, there is a family of endogenous mammalian ligands described currently that activate these receptors called the urocortins.…”

Corticotropin-releasing hormone: An autocrine hormone that promotes lipogenesis in human sebocytes

“…One microgram of total RNA from SZ95 sebocytes treated with Dnase I (GenHunter, Nashville, TN) were reverse transcribed to cDNA by using the Thermoscript reverse transcriptase (GIBCO͞BRL) with random hexamers as primers in a 20-l reaction solution. To quantify expression of CRH-R1, CRH-R2, and ⌬ 5 -3␤-HSD mRNA, real time quantitative RT-PCR (TaqMan PCR; PE Applied Biosystems) using a Perkin-Elmer 7700 sequence detector was performed (12). The reaction contained 1ϫ TaqMan Universal PCR Master Mix (PE Applied Biosystems), 900 nM of the forward and reverse primers, and 200 nM of TaqMan probes.…”

PET Imaging of CRF1 with [11C]R121920 and [11C]DMP696: is the target of sufficient density?

“…In the rodent, CRF1 mediates effects on the HPA axis and anxiety-related behaviors [6] and CRF2 affects feeding behaviors [7]. There are important species differences in the distributions of mRNA and protein of these two receptors between non-human primate and rodent [8,9]. In pituitary, CRF1 protein level depends on post-transcriptional regulatory mechanisms [10] suggesting dissociation of protein density from mRNA level for this receptor.…”