NEUROENDOCRINE FUNCTIONS OF VASOPRESSIN AND VASOPRESSIN RECEPTORS

加压素和加压素受体的神经内分泌功能

• 批准号: 7734812
• 负责人: Greti Aguilera
• 金额: $ 36.76万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7734812
• 关键词: Address; Affect; Anterior Pituitary Gland; Apoptosis; Apoptotic; Area; Bad protein; Blood Circulation; Blood Pressure; Brain; CRH gene; Calmodulin; Caspase; Cell Line; Cell membrane; Chronic; Chronic stress; Condition; Corticotropin; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Dominant-Negative Mutation; Extracellular Signal Regulated Kinases; HPSE gene; Hypothalamic structure; Laboratory Study; MEKs; Mediating; Mediator of activation protein; Mitogen-Activated Protein Kinases; Molecular; Neuronal Plasticity; Neurons; Neuropeptides; Neurosecretory Systems; Pathway interactions; Peptides; Phosphorylation; Physiological; Pituitary Gland; Protein Dephosphorylation; Protein Kinase C; Protein Kinase C Alpha; Purpose; Role; Serum; Signal Transduction; Stress; System; Vasopressin Receptor; Vasopressins; caspase-3; deprivation; hypothalamic-pituitary-adrenal axis; inhibitor/antagonist; parvocellular; prevent; pro-apoptotic protein; protein kinase C beta; protein kinase C kinase; protein kinase C-delta; receptor; water conservation

Summary: In addition to its recognized actions on water conservation and blood pressure, the neuropeptide vasopressin is released into the pituitary portal circulation and within distinct brain areas during stressful challenges. The neuroendocrine effects of vasopressin are mediated by specific receptor of subtype V1b in the anterior pituitary and V1a and V1b subtypes in the brain. Vasopressin produced by parvocellular neurons of the PVN potentiates the stimulatory effect of CRH on pituitary ACTH secretion acting through plasma membrane receptors of the V1b subtype (V1bR). During prolonged activation of the HPA axis there is a predominant increase in VP in parvocellular hypothalamic neurons and pituitary V1b receptors compared with CRH and CRH receptors, suggesting that VP becomes the main mediator of pituitary corticotroph responsiveness during chronic stress. However, studies of this laboratory have shown that VP has little impact on HPA axis activity in chronic stress conditions but that the neuropeptide mediates mitogenic effects in the pituitary and has potential neuroprotective effects during stress adaptation. Studies in the neuronal cell line H32, which expresses endogenous V1 VP receptors, showed that activation of endogenous V1 VP receptors prevents serum deprivation-induced apoptosis, through phosphorylation-inactivation of the pro-apoptotic protein, Bad, and consequent decreases in cytosolic cytochome c and caspase-3 activation. These actions of VP are mediated by mitogen activated protein (MAP) kinase and extracellular signal-regulated kinases (ERK), but also involves Ca2+/calmodulin dependent kinase (CaMK) and protein kinase C (PKC). Additional studies were performed to role of protein kinase C signaling on the antiapoptotic effects of VP in neurons using the cell line H32. Serum deprivation for 6h induced caspase 3 activity and dephosphorylation of the proapoptotic protein, Bad, while co-incubation with VP reversed these changes. The selective PKC subtypes alpha/beta inhibitor, G6976, or PKC alpha and beta dominant-negatives reduced the effect of VP on caspase activation, while PKC delta inhibitors or dominant-negative reduced serum deprivation-induced caspase-3 activity, without affecting the protective action of VP. Consistently, serum deprivation increased PKC delta but not PKC alpha or PKC beta activity, while VP increased PKC alpha and PKC beta activity without affecting PKC delta activity. VP-induced Bad phosphorylation was reduced by PKC alpha and beta or MEK inhibitors, but totally blocked by both inhibitors combined. However, total inhibition of caspase 3 activation required additional inhibition of the PI3K/Akt pathway. The data demonstrate differential roles of PKC subtypes, with PKC delta mediating the apoptotic effect of serum deprivation, and PCK alpha and beta together with the MAP kinase and PI3K/Akt pathways mediating the antiapoptotic actions of VP.

摘要：除了公认的节水和血压作用外，神经肽加压素还被释放到垂体门户循环中，并在压力挑战期间在不同的大脑区域内释放到不同的大脑区域内。加压素的神经内分泌作用是由脑垂体前体V1b的特异性受体和大脑中V1A和V1B亚型的特异性受体介导的。 PVN的副细胞神经元产生的加压素增强了CRH对通过V1B亚型（V1BR）的质膜受体作用的垂体ACTH分泌的刺激作用。与CRH和CRH受体相比，在长期激活HPA轴的激活过程中，VP主要增加了VP和垂体V1B受体，这表明VP成为慢性应激过程中垂体皮质营养的主要介体。然而，该实验室的研究表明，VP对慢性应激条件下的HPA轴活动几乎没有影响，但是神经肽在垂体中介导有丝分裂作用，并且在压力适应期间具有潜在的神经保护作用。 表达内源性V1 VP受体的神经元细胞系H32中的研究表明，内源性V1 VP受体的激活通过促凋亡蛋白的磷酸化灭活，不良的磷酸化诱导，可阻止血清剥夺引起的凋亡，不良，且导致细胞chosocolocic pytotosolic odtotosolic odtotosolic codtocosolic codtochome capase c和caspase-3激素中的降低。 VP的这些作用是由有丝分裂原活化蛋白（MAP）激酶和细胞外信号调节激酶（ERK）介导的，但还涉及Ca2+/钙调蛋白依赖蛋白激酶（CAMK）和蛋白激酶C（PKC）。进行了其他研究，以使用细胞系H32进行蛋白激酶C信号传导对VP的抗凋亡作用的作用。 6H诱导caspase 3活性和促凋亡蛋白的脱磷酸化的血清剥夺不良，而与VP共孵育却逆转了这些变化。选择性PKC亚型Alpha/beta抑制剂G6976或PKC Alpha和Beta主导性降低了VP对CASPase激活的影响，而PKC Delta抑制剂或优势 - 阴性降低了血清剥夺降低血清剥夺诱导的caspase-3活性，而无需影响保护性动作。一致地，血清剥夺增加了PKC Delta，但不增加PKC Alpha或PKC Beta活性，而VP增加了PKC Alpha和PKC Beta活性，而不会影响PKC Delta活性。 PKC Alpha和Beta或MEK抑制剂降低了VP诱导的不良磷酸化，但两种抑制剂的总和都完全阻塞。但是，caspase 3激活的总抑制需要对PI3K/AKT途径进行额外抑制。数据显示了PKC亚型的差异作用，PKC Delta介导了血清剥夺的凋亡效应，PCK Alpha和beta以及MAP激酶以及PI3K/AKT途径介导了VP的抗凋亡作用。