Regulation of Vasopressin Secretion

对该项目的两年支持将使我们能够进行原申请目标3和4中提出的实验。在美国心脏协会的支持下，我们已经能够完成目标1和2的大部分内容，这支持了我们的假设，即同时将视上神经元（SON）暴露于ATP和苯肾上腺素诱导向非脱敏性离子型嘌呤能受体亚型转变，使ATP能够维持加压素（VP）释放数小时。这项工作已提交出版。AHA基金不支持目标3和4，这两个目标对于理解去甲肾上腺素诱导嘌呤能受体亚型转变的机制至关重要：目标3侧重于鉴定SON中苯肾上腺素激活的β 1-肾上腺素能受体亚型，目标4将鉴定SON中苯肾上腺素激活的信号级联。识别β 1-R信号级联对于理解为什么ATP激活代谢型嘌呤能受体不会诱导与苯肾上腺素相同的效应至关重要。苯肾上腺素诱导对ATP的持续反应的能力是重要的，因为它为稳态CNS调节系统提供了一种机制，以产生延长的反应，例如，以恢复出血后的血容量或持续的唤醒。

Two years of support for this project will allow us to perform the experiments proposed in Aims 3 and 4 of the original application. We have been able to complete the bulk of Aims 1 and 2 with support from the American Heart Assoc. This supported our hypothesis that simultaneous exposure of supraoptic neurons (SON) to ATP and phenylephrine induces a shift to non-desensitizing ionotropic purinergic receptor subtypes that allow ATP to sustain vasopressin (VP) release for hours. This work has been submitted for publication. The AHA grant does not provide support for Aims 3 and 4 which are crucial to understanding the mechanism by which norepinephrine can induce the shift in purinergic receptor subtype: Aim 3 is focused on identifying the 1-adrenergic receptor subtype activated by phenylephrine in SON and Aim 4 will identify the signal cascades activated by phenylephrine in SON. Identifying the 1-R signal cascade is critical to understanding why ATP activation of metabotropic purinergic receptors does not induce the same effect as phenylephrine. The ability of phenylephrine to induce sustained responses to ATP is important, because it provides a mechanism for homeostatic CNS regulatory systems to mount extended responses in order, for example, to restore blood volume following hemorrhage or for sustained arousal.