Sex differences in the corticotropin-releasing factor receptor

描述（由申请人提供）：与压力有关的精神疾病，如抑郁症和焦虑症，在女性中比男性更普遍。促肾上腺皮质激素释放因子（CRF）是一种协调应激反应的神经肽，其功能障碍与抑郁症和焦虑症有关。然而，通用报告格式系统中的性别差异没有得到很好的描述。我们实验室最近的工作确定了神经元对CRF反应的性别差异。具体而言，蓝斑（LC）神经元CRF的突触后敏感性更大的雌性大鼠与雄性大鼠。此外，游泳应激致敏LC神经元CRF的雄性大鼠。以下建议将扩展这些发现，以确定这些差异的潜在细胞机制。具体目的如下：1）确定CRF受体偶联和信号传导的性别差异。CRF受体免疫沉淀将用于确定在应激和非应激条件下不同G蛋白与CRF受体偶联是否存在性别差异。此外，将使用PKA和PKC测定评价CRF受体信号传导的性别差异。初步数据表明，CRF受体更强烈地耦合到Gs蛋白在无压力的女性相比，无压力的男性。游泳应激后，Gs耦合到CRF受体的增加只在男性。这是第一个表明受体与不同G蛋白偶联存在性别差异的数据。CRF受体结构和功能的性别差异可能导致女性应激易感性增加。2)确定压力后CRF受体运输的性别差异。在这里，我们将使用CRF受体的免疫沉淀，沿着与免疫电子显微镜，以确定是否CRF受体的贩运不同，在雄性与雌性大鼠后的压力。初步数据表明，压力后，女性CRF受体内化可能会被抑制。如果得到支持，这将表明雌性大鼠缺乏这种补偿性应激反应。与公共卫生有关的妇女患与压力有关的精神疾病的可能性是男子的两倍，如抑郁症和焦虑症。拟议的实验将确定CRF受体的性别差异，CRF是一种重要的应激神经调节剂，这可能是女性对应激和应激相关病理学的脆弱性增加的基础。重要的是，由于CRF拮抗剂正在开发用于治疗抑郁症和焦虑症，CRFr的性别差异可能会影响这些化合物在女性中的疗效。

DESCRIPTION (provided by applicant): Stress-related mental illnesses, such as depression and anxiety disorders, are more prevalent in women than men. Dysfunctions in corticotropin-releasing factor (CRF), the neuropeptide that orchestrates the stress response, have been linked to depression and anxiety disorders. However, sex differences in the CRF system are not well characterized. Recent work from our laboratory identified sex differences in neuronal responses to CRF. Specifically, postsynaptic sensitivity of locus coeruleus (LC) neurons to CRF was greater in female vs. male rats. Moreover, swim stress sensitized LC neurons to CRF in male rats only. The following proposal will expand on these finding to determine the underlying cellular mechanism of these differences. The specific aims are as follows: 1) Identify sex differences in the coupling and signaling of the CRF receptor. CRF receptor immunoprecipitation will be used to determine whether there are sex differences in coupling of different G-proteins to the CRF receptor under stressed and unstressed conditions. Additionally, sex differences in CRF receptor signaling will be evaluated by using PKA and PKC assays. Preliminary data indicate that the CRF receptor is coupled more strongly to the Gs protein in unstressed females compared to unstressed males. Following swim stress, Gs coupling to the CRF receptor increases in males only. These are the first data to suggest sex differences in the coupling of a receptor to different G-proteins. Sex differences in CRF receptor structure and function may contribute to increased stress-susceptibility in women. 2) Identify sex differences in CRF receptor trafficking following stress. Here we will use immunoprecipitation of the CRF receptor, along with immunoelectron microscopy to determine whether the CRF receptor is trafficked differently in male vs. female rats after stress. Preliminary data suggest that following stress, CRF receptor internalization in females may be comprimised. If supported, this would suggest that female rats lack this compensatory stress response. PUBLIC HEALTH RELEVANCE Women are twice as likely to suffer from stress-related psychiatric disorders, like depression and anxiety disorders, as men. The proposed experiments will identify sex differences in the receptor for CRF, an important neuromodulator of stress, which may underlie the increased vulnerability of females to stress and stress-related pathology. Importantly, because CRF antagonists are being developed to treat depression and anxiety disorders, sex differences in the CRFr could impact the efficacy of these compounds in women.