Regulation of Vasopressin Secretion

这个项目两年的支持将使我们能够执行原始申请的目标3和目标4中提出的实验。在美国心脏协会的支持下，我们已经完成了目标1和目标2的大部分。这支持了我们的假设，即视上神经元（SON）同时暴露于ATP和苯肾上腺素诱导向非脱敏的嗜离子嘌呤能受体亚型转变，使ATP维持抗利尿激素（VP）释放数小时。这项工作已提交出版。美国心脏协会的资助不支持Aims 3和4，这对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：Aims 3的重点是鉴定SON中由苯肾上腺素激活的1-肾上腺素能受体亚型，Aim 4将鉴定SON中由苯肾上腺素激活的信号级联。确定1-R信号级联对于理解为什么ATP激活代谢嘌呤能受体不会诱导与苯肾上腺素相同的效果至关重要。苯肾上腺素诱导对ATP的持续反应的能力很重要，因为它提供了一种机制，使体内平衡的中枢神经系统调节系统能够产生延长的反应，例如，在出血后恢复血容量或持续唤醒。

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.