Regulation of Vasopressin Secretion

对这个项目的两年支持将使我们能够执行最初申请的目标3和4中提出的实验。在美国心脏协会的支持下，我们已经完成了AIMS 1和2的大部分工作。这支持了我们的假设，即视上神经元(SON)同时暴露于ATP和苯肾上腺素可诱导向非脱敏的离子型嘌呤能受体亚型的转变，从而允许ATP维持加压素(VP)的释放达数小时。这部作品已提交出版。AHA拨款不支持AIMS 3和AIMS 4，它们对于理解去甲肾上腺素可以诱导嘌呤能受体亚型转变的机制至关重要：AIMS 3专注于识别SON中由苯肾上腺素激活的1-肾上腺素能受体亚型，AIM 4将识别由苯肾上腺素激活的SON中的信号级联。识别ATP1-R信号级联对于理解为什么代谢性嘌呤能受体的激活不能产生与苯肾上腺素相同的作用是至关重要的。苯肾上腺素诱导对ATP的持续反应的能力很重要，因为它为体内平衡的中枢神经系统提供了一种机制，以启动延伸反应，例如，恢复出血后的血量或持续唤醒。

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.