Modulation of parasympathetic neurons by PACAP peptides

描述（由申请人提供）：腺苷酸环化酶激活 PACAP多肽是一种有效的心血管调节神经肽。我们 假设PACAP作用的关键部位在外周 作为局部整合中心的心脏副交感神经节。在 豚鼠心脏副交感神经节，所有节后神经元均为 由PACAP免疫反应性纤维支配，PACAP肽有效地 兴奋性增强。的 豚鼠心脏副交感神经元膜兴奋性增加 由PACAP产生的比任何其他研究的神经肽产生的都要大， 日期，但负责PACAP诱导的去极化和 兴奋性增加是未知的。 该项目的主要目标是建立 PACAP对豚鼠心肌兴奋性和去极化的影响 神经元提出了以下具体目标。 目的1：建立第二信使转导级联， 产生PACAP诱导的膜兴奋性增加， 去极化 目的2：建立PACAP诱导的细胞膜离子机制。 膜兴奋性增加。 目的3：建立PACAP诱导的细胞膜离子机制 内向电流 目的4：确定PACAP是否诱导细胞内钙离子升高 (Ca2心肌神经元内的Ca ~（2+）i既可由Ca ~（2+）内流产生，也可由Ca ~（2+）释放产生 从IP 3或ryanodine敏感的商店，并测试是否上升（Ca 2+）， 是膜去极化产生的初始步骤，或者 增加兴奋性。 这些实验的结果将提供关键的，新的洞察机制 测定PACAP诱导的对副交感神经中神经元的兴奋作用 心脏神经节;决定副交感神经 抑制驱动心脏功能。

DESCRIPTION (provided by applicant): Pituitary adenylate cyclase activating polypeptides (PACAP) are potent cardiovascular regulatory neuropeptides. We hypothesize that a critical site of PACAP action is within the peripheral parasympathetic cardiac ganglia that serve as local integrative centers. In guinea pig parasympathetic cardiac ganglia, all postganglionic neurons are innervated by PACAP-immunoreactive fibers, and PACAP peptides potently depolarize and increase excitability of the postganglionic cardiac neurons. The increase in membrane excitability of guinea pig cardiac parasympathetic neurons by PACAP is greater than that produced by any other neuropeptide studied to date, but mechanism(s) responsible for the PACAP-induced depolarization and increase in excitability are not known. The primary goal of the project is to establish the mechanisms underlying the PACAP-induced increase in excitability and depolarization of guinea pig cardiac neurons. The following specific aims are proposed. Aim 1: Establish the second messenger transduction cascades responsible for generation of the PACAP-induced increase in membrane excitability and depolarization. Aim 2: Establish the membrane ionic mechanisms underlying the PACAP-induced increase in membrane excitability. Aim 3: Establish the membrane ionic mechanisms generating the PACAP-induced inward current. Aim 4: Establish whether the PACAP-induced rise in intracellular calcium (Ca2+)i in cardiac neurons occurs from either Ca2+ influx or from Ca2+ release from IP3- or ryanodine-sensitive stores, and test whether the rise in (Ca2+)i is an initial step in the generation of the membrane depolarization or increased excitability. The results of these experiments will provide key, new insight into mechanisms determining PACAP-induced excitatory actions on neurons in the parasympathetic cardiac ganglia; ganglia that determine the extent of parasympathetic inhibitory drive on cardiac function.