CENTRAL REGULATION OF ADRENOCORTICOTROPIN SECRETION

促肾上腺皮质激素释放因子(CRF-41)产生的核周 下丘脑室旁核(PPVN)起整体作用 促肾上腺皮质激素(ACTH)的调节作用 分泌、前阿片黑素皮质素(POMC)基因表达，从而在 肾上腺皮质分泌的调节。的分泌活动 CRF阳性神经元受体液因子(糖皮质激素、 葡萄糖等)和许多传递信息的传入纤维 内感和外感刺激。CRF-41神经元接受重压 来自髓细胞群的神经支配，这些髓质细胞群本身接受 不同的内脏和躯体感觉输入阵列。因此，他们是 调解激活的优秀候选人 下丘脑-垂体-肾上腺(HPA)轴对多种因素的反应 内脏刺激(如低血容量、低血压)和躯体刺激(如疼痛)。 来自延髓区域的差异是输入的主要来源 含有去甲肾上腺素(NE)、肾上腺素(EPI)、神经肽Y(NPY)、 和一种具有激活素样免疫反应性的多肽(IbetaA-Li) 富含CRF的pPVN。这些假定的递质通常有助于CRF-41 分泌，尽管肾上腺素能受体亚型的性质介导 儿茶酚胺的作用仍然存在争议。归根结底，机制必须 以确保基因表达和分泌的协调。在 目前的提议，我们将检验假设，单独或在 NE和IbetaA-Li(转化生长因子-β生长因子的成员)的组合 家族)参与CRF-41分泌和基因的协调 表情。因为这些发射器的生物化学多样性 以及它们以特定方式释放的可能性 取决于刺激特性(形态，幅度， 频率、持续时间)，我们假设这些发射器 差异影响靶细胞的分泌和基因表达 通过多条细胞内途径。神经递质释放唤起 神经元的快速和缓慢反应，因此允许立即 对刺激的反应以及较长期的适应性可塑性。它 已经提出，c-fos基因的诱导，编码一种 具有DNA结合特性的核磷蛋白与 转录调节因子，是信号级联的一个组成部分，通过 哪些特定的递质可能调节神经元基因的表达。 因此，我们将评估这些神经递质中是否有 激活c-fos基因，然后确定c-fos是否 激活与CRF-41的分泌和/或基因表达有关。

Corticotropin releasing factor (CRF-4l)-producing perikarya in the hypothalamic parvocellular paraventricular nuclei (pPVN) play an integral role in regulation of adenohypophysial adrenocorticotropin (ACTH) secretion, pro-opiomelanocortin (POMC) gene expression and, thus, in the regulation of adrenocortical secretion. The secretory activity of CRF-positive neurons is modulated by humoral factors (glucocorticoids, glucose, etc) and by numerous afferent fibers conveying information about interoceptive and exteroceptive stimuli. CRF-41 neurons receive heavy innervation from medullary cell groups which, themselves, receive a diverse array of visceral and somatosensory inputs. Therefore they are excellent candidates for mediating activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to a number of visceral (e.g. hypovolemia, hypotension) and somatic (e.g. pain) stimuli. Efferents from medullary regions are the major source of inputs containing norepinephrine (NE), epinephrine (EPI), neuropeptide Y (NPY), and a peptide with activin-like immunoreactivity (IbetaA-LI) to the CRF-rich pPVN. These putative transmitters generally facilitate CRF-41 secretion, although the nature of adrenergic receptor subtypes mediating catecholamine actions remain controversial. Ultimately, mechanisms must exist to ensure coordination of gene expression and secretion. In the present proposal, we will test the hypothesis that, individually or in combination, NE and IbetaA-LI (a member of the TGF-beta growth factor family) participate in the coordination of CRF-41 secretion and gene expression. Because of the biochemical diversity of these transmitters and the likelihood that their release occurs in a specific manner dependent upon the stimulus characteristics (modality, amplitude, frequency, duration), we hypothesize that these transmitters differentially affect secretion and gene expression in the target cells via multiple intracellular pathways. Neurotransmitter release evokes both rapid and slow responses in neurons, thus permitting an immediate response to the stimulus as well as longer-term adaptive plasticity. It has been suggested that induction of the c-fos gene, which encodes a nuclear phosphoprotein with DNA binding properties consistent that of a transcriptional regulator, is a component of the signaling cascade by which specific transmitters may modulate neuronal gene expression. Therefore, we will evaluate whether any of these neurotransmitters activate the c-fos gene and then determine whether or not C-fos activation is correlated with CRF-41 secretion and/or gene expression.