DYNAMIC CALCIUM REGULATION IN AIRWAY SMOOTH MUSCLE

描述：细胞内钙([Ca~(2+)]i)调节许多细胞内的 气道平滑肌(ASM)对激动剂刺激的反应。 首席调查员实验室最近的研究表明， 乙酰胆碱(Ach)和内皮素-1等激动剂诱导[钙]i 猪ASM细胞中反映重复钙释放的振荡 通过肌浆网的兰尼定受体(RyR)通道 (Sr)对非平滑肌组织的研究表明，环状ADP 核糖(CADPR)是b-NAD的代谢产物，是RyR激活的介质。 与这项提议相关的初步研究也表明，1)cadpr是 激动剂刺激后ASM细胞产生的cADPR诱导SR 3)cADPR及其拮抗剂的调节作用 激动剂诱导的[Ca~(2+)]i振荡。其他研究也表明， [CA2]i振荡是对增加的响应进行频率调制的 激动剂浓度以及cADPR。较慢的钙依赖细胞 强制生产等过程有效地集成了更快的[钙]i 震荡。拟议研究的总体假设是cadpr， 通过Ry通道影响肌质网钙释放，介导激动剂诱导 [CA2]i在猪ASM细胞中的振荡。中国的长期目标是 建议的研究是为了了解信号转导途径 基础激动剂诱导ASM细胞SR[Ca~(2+)]i释放。建议数 研究将确定[Ca~(2+)]i对Ach和ET-1的反应 刺激单个ASM细胞，并确定cADPR I[Ca~(2+)]I的作用 ASM细胞的调节。

DESCRIPTION: Intracellular Ca2+ ([Ca2+]I) regulates a number of cellular processes in airway smooth muscle (ASM) in response to agonist stimulation. Recent studies from the principal investigator's laboratory indicate that agonists such as acetylcholine (Ach) and endothelin-1 induce [Ca2+]I oscillations in porcine ASM cells that reflect repetitive Ca2+ release through ryanodine receptor (RyR) channels of the sarcoplasmic reticulum (SR). Studies in non-smooth muscle tissue have demonstrated that cyclic ADP ribose (cADPR), metabolite of b-NAD, is a mediator for RyR activation. Preliminary studies related to this proposal also indicate that 1) cADPR is produced in ASM cells following agonist stimulation, 2) cADPR induces SR Ca2+ release through RyR channels, and 3) cADPR and its antagonist modulate agonist-induced [Ca2+]I oscillations. Additional studies also indicate that [Ca2+]I oscillations are frequency modulated in response to increasing agonist concentration as well as by cADPR. Slower Ca2+ -dependent cellular processes such as force production effectively integrate the faster [Ca2+]I oscillations. The overall hypothesis of the proposed studies is that cADPR, by affecting SR Ca2+ release through Ry channels, mediates agonist-induced [Ca2+]I oscillations in porcine ASM cells. The long-term goal of the proposed studies is to understand the signal transduction pathways underlying agonist-induced SR [Ca2+]I release in ASM cells. The proposed studies will determine the [Ca2+]I response to Ach and endothelin-1 stimulation in single ASM cells, and identify the role of cADPR i [Ca2+]I) regulation in ASM cells.