Sex differences in the corticotropin‐releasing factor receptor and its regulation by stress

Abstract

Depression, a common stress‐related mental illness, affects twice as many women as men. Dysfunctions in corticotropin‐releasing factor (CRF) have been linked to depression, but sex differences in the CRF system are not well characterized. Previous studies from our laboratory demonstrated that the postsynaptic sensitivity of locus coeruleus (LC) neurons to CRF was greater in female vs. male rats. Moreover, prior stress sensitized LC neurons of male but not female rats. These findings suggested the existence of sex differences in CRF receptor (CRFr) coupling and regulation. To test this, the CRFr was immunoprecipitated from cortical samples of stressed (15min swim) or handled male and female rats. Under unstressed conditions, the CRFr is more highly coupled to Gs in females vs. males. Stress increases coupling of CRFr to Gs in male but not female rats. Additionally, we found that following stress, CRFr association with βarrestin2— which targets the CRFr for desensitization and internalization—was increased in male but not female rats. Thus, sex differences in CRFr coupling and/or desensitization may contribute to differential neuronal sensitivity of females to CRF and stress. This may translate to increased vulnerability of females to depression. Finally, sex differences in CRFr should be considered in the development of CRF antagonists as therapeutic agents. Supported by PHS Grants MH 40008 and MH 63267 to RJV.