Electrophysiological Correlates of Vasopressin Secretion

哺乳动物神经分泌神经元是研究中枢神经系统锋电位放电模式与激素/递质释放之间关系的理想模型。神经分泌神经元 采用促进神经末梢处最有效的刺激-分泌耦合的爆发模式。加压素神经元中的阶段性爆发活动是这种模式的示例，并且相对独特，因为它可以在体外研究，因为它主要是由内在膜特性引起的。这一提议的总体假设是，相位爆发本身可以在很大程度上解释的理解一个初级电流，其调制的Ca++，其自身调节的强啡肽通过Kopiate受体。 具体目标是： 目的1）确定离子种类，电导变化的基础，以及DAP（IDAP）电流的Ca++依赖性。 模型模拟在过去的赠款期间开发的阶段性活动。我们预测，平台电位潜在的爆发的结果从Ca++依赖性抑制的K+泄漏电流，使该电流达到电压依赖性升高[Ca++]。 目的2）探讨Kopiate受体对VP神经元的自身调节抑制机制。我们预测，在加压素神经元爆发期间局部释放的强啡肽改变了Ca++敏感性， 的K+漏电流，提高其阈值，并终止突发。 目的3）在体外研究自发调节在时相爆发表达变异中的作用。我们预测，相位爆裂与强啡肽调节DAP和爆裂长度和互补的能力，相位爆裂活动的赤字是由于赤字的自动调节。一个推论是，相位爆发可能与树突乔木存在的程度。 了解相位爆发的起源对于了解VP释放在生理和病理生理条件下是如何控制的至关重要。VP释放对正常的水平衡和心血管调节至关重要。

Mammalian neurosecretory neurons are excellent models for understandingthe relationship between spike discharge patterns and hormone/transmitter release in the central nervous system. Neurosecretory neurons adopt a bursting pattern that promotes maximally efficient stimulus-secretion coupling at the nerve terminal. The phasic bursting activity in vasopressin neurons is exemplary of this pattern, and relatively unique in ihat it can be studied in vitro, as it results largely from intrinsic membrane properties. The global hypothesis of this proposal is that phasic burstingper se can be explained largely by the understanding of one primary current, its modulation by Ca++, and its autoregulation by dynorphin through Kopiate receptors. The Specific Aims are: Aim 1) Determine the ion species, underlyingconductance change, and Ca++-dependence of the current underlying the DAP (IDAP)- Experimentally, we will test several predictions from a powerful computational model simulating phasic activity developed during the past grant period. We predict that the plateau potential underlying bursts results from a Ca++ dependent inhibition of a K+ leak current, such that this current attains voltage-dependence in elevated [Ca++].. Aim 2) Determine the mechanism of the autoregulatory inhibition of VP neurons via Kopiate receptors. We predict that dynorphin, released locally during a burst from vasopressin neurons, shifts the Ca++ sensitivity of a K+ leak current rightward, raising its threshold, and terminating the burst. Aim 3) Determine the role of autoregulation in the variability of phasic bursting expression in vitro. We predict that phasic bursting is correlated with the ability of dynorphin to regulate the DAP and burst length and complimentarily, that deficits in phasic bursting activity are due to deficits in autoregulation. A corollary is that phasic bursting may be related to the degree of dendritic arbor present. Understanding the origin of phasic bursting is critical to understanding how VP release is controlled in both physiological and pathophysiological conditions. VP release is critical to normal water balance and cardiovascular regulation.