Molecular Psychiatry 15, 877 (September 2010) | doi:10.1038/mp.2010.89

Răspunsul diferit în funcție de sex la semnalizarea prin CRF (corticotropin-releasing factor)

D A Bangasser, A Curtis, B A S Reyes, T T Bethea, I Parastatidis, H Ischiropoulos, E J Van Bockstaele and R J Valentino


În acest articol se ilustrează schematic funcționarea diferită a receptorului pentru CRF. Acest receptor se cuplează cu o proteina G. Legarea de Gs este mai puternică la neuronii unei femei în comparație cu cei de la un bărbat. Acest fenomen ar putea avea ca urmare creșterea semnalizării intracelulare ca răspuns la stress la sexul feminin.

Although the higher incidence of stress-related psychiatric disorders in females is well documented, its basis is unknown. Here, we show that the receptor for corticotropin-releasing factor (CRF), the neuropeptide that orchestrates the stress response, signals and is trafficked differently in female rats in a manner that could result in a greater response and decreased adaptation to stressors. Most cellular responses to CRF in the brain are mediated by CRF receptor (CRFr) association with the GTP-binding protein, Gs. Receptor immunoprecipitation studies revealed enhanced CRFr-Gs coupling in cortical tissue of unstressed female rats. Previous stressor exposure abolished this sex difference by increasing CRFr-Gs coupling selectively in males. These molecular results mirrored the effects of sex and stress on sensitivity of locus ceruleus (LC)-norepinephrine neurons to CRF. Differences in CRFr trafficking were also identified that could compromise stress adaptation in females. Specifically, stress-induced CRFr association with β-arrestin2, an integral step in receptor internalization, occurred only in male rats. Immunoelectron microscopy confirmed that stress elicited CRFr internalization in LC neurons of male rats exclusively, consistent with reported electrophysiological evidence for stress-induced desensitization to CRF in males. Together, these studies identified two aspects of CRFr function, increased cellular signaling and compromised internalization, which render CRF-receptive neurons of females more sensitive to low levels of CRF and less adaptable to high levels of CRF. CRFr dysfunction in females may underlie their increased vulnerability to develop stress-related pathology, particularly that related to increased activity of the LC-norepinephrine system, such as depression or post-traumatic stress disorder.