DYNAMIC CALCIUM REGULATION IN AIRWAY SMOOTH MUSCLE

描述：细胞内Ca 2+（[Ca 2 +]I）调节许多细胞内的钙离子， 气道平滑肌（ASM）对激动剂刺激的反应过程。 首席研究员实验室的最新研究表明， 激动剂如乙酰胆碱（Ach）和内皮素-1诱导[Ca 2 +]I 猪ASM细胞中的振荡反映了重复的Ca 2+释放 通过肌浆网的RyR通道 （SR）。 在非平滑肌组织中的研究表明， 核糖（cADPR），b-NAD的代谢物，是RyR活化的介体。 与该提议相关的初步研究还表明：1）cADPR是 激动剂刺激后ASM细胞中产生，2）cADPR诱导SR Ca 2+通过RyR通道释放，以及3）cADPR及其拮抗剂调节 激动剂诱导的[Ca 2 +]I振荡。 其他研究还表明， [Ca2+]I振荡是响应于增加的 激动剂浓度以及cADPR。 慢钙依赖性细胞 过程，如生产力有效地整合更快的[Ca 2 +]I 振荡 所提出的研究的总体假设是cADPR， 通过Ry通道影响SR Ca 2+释放，介导激动剂诱导的 [Ca2猪ASM细胞中的+]I振荡。 的长期目标 研究的目的是了解信号转导途径 潜在的激动剂诱导的SR [Ca 2 +]I释放在ASM细胞。 拟议 研究将确定[Ca 2 +]I对Ach和内皮素-1的反应， 刺激单个ASM细胞，并确定cADPR（[Ca 2 +]I）的作用 ASM细胞中的调节。

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.