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首页> 外文期刊>The Yale Journal of Biology and Medicine >Signal transduction in esophageal and LES circular muscle contraction.
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Signal transduction in esophageal and LES circular muscle contraction.

机译：食管和LES环形肌肉收缩中的信号转导。

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摘要

Contraction of normal esophageal circular muscle (ESO) in response to acetylcholine (ACh) is linked to M2 muscarinic receptors activating at least three intracellular phospholipases, i.e., phosphatidylcholine-specific phospholipase C (PC-PLC), phospholipase D (PLD), and the high molecular weight (85 kDa) cytosolic phospholipase A2 (cPLA2) to induce phosphatidylcholine (PC) metabolism, production of diacylglycerol (DAG) and arachidonic acid (AA), resulting in activation of a protein kinase C (PKC)-dependent pathway. In contrast, lower esophageal sphincter (LES) contraction induced by maximally effective doses of ACh is mediated by muscarinic M3 receptors, linked to pertussis toxin-insensitive GTP-binding proteins of the G(q/11) type. They activate phospholipase C, which hydrolyzes phosphatidylinositol bisphosphate (PIP2), producing inositol 1,4,5-trisphosphate (IP3) and DAG. IP3 causes release of intracellular Ca++ and formation of a Ca++-calmodulin complex, resulting in activation of myosin light chain kinase and contraction through a calmodulin-dependent pathway. Signal transduction pathways responsible for maintenance of LES tone are quite distinct from those activated during contraction in response to maximally effective doses of agonists (e.g., ACh). Resting LES tone is associated with activity of a low molecular weight (approximately 14 kDa) pancreatic-like (group 1) secreted phospholipase A2 (sPLA2) and production of arachidonic acid (AA), which is metabolized to prostaglandins and thromboxanes. These AA metabolites act on receptors linked to G-proteins to induce activation of PI- and PC-specific phospholipases, and production of second messengers. Resting LES tone is associated with submaximal PI hydrolysis resulting in submaximal levels of inositol trisphosphate (IP3-induced Ca++ release, and interaction with DAG to activate PKC. In an animal model of acute esophagitis, acid-induced inflammation alters the contractile pathway of ESO and LES. In LES circular muscle, after induction of experimental esophagitis, basal levels of PI hydrolysis are substantially reduced and intracellular Ca++ stores are functionally damaged, resulting in a reduction of resting tone. The reduction in intracellular Ca++ release causes a switch in the signal transduction pathway mediating contraction in response to ACh. In the normal LES, ACh causes release of Ca++ from intracellular stores and activation of a calmodulin-dependent pathway. After esophagitis, ACh-induced contraction depends on influx of extracellular Ca++, which is insufficient to activate calmodulin, and contraction is mediated by a PKC-dependent pathway. These changes are reproduced in normal LES cells by thapsigargin-induced depletion of Ca++ stores, suggesting that the amount of Ca++ available for release from intracellular stores defines the signal transduction pathway activated by a maximally effective dose of ACh.
机译：响应于乙酰胆碱（ACh）的正常食管环形肌（ESO）的收缩与激活至少三个细胞内磷脂酶的M2毒蕈碱受体相关，即磷脂酰胆碱特异性磷脂酶C（PC-PLC），磷脂酶D（PLD）和高分子量（85 kDa）的胞质磷脂酶A2（cPLA2）诱导磷脂酰胆碱（PC）代谢，生成二酰基甘油（DAG）和花生四烯酸（AA），从而激活蛋白激酶C（PKC）依赖性途径。相反，最大有效剂量的ACh诱导的食管下括约肌（LES）收缩是由毒蕈碱M3受体介导的，与M（q / 11）型百日咳毒素不敏感的GTP结合蛋白有关。它们激活磷脂酶C，后者水解磷脂酰肌醇双磷酸酯（PIP2），产生肌醇1,4,5-三磷酸酯（IP3）和DAG。 IP3导致细胞内Ca ++的释放和Ca ++-钙调蛋白复合物的形成，从而导致肌球蛋白轻链激酶的激活和钙调蛋白依赖性途径的收缩。响应于最大有效剂量的激动剂（例如，ACh），负责维持LES音调的信号转导途径与在收缩期间激活的那些信号转导途径完全不同。静止的LES音与低分子量（约14 kDa）胰腺样（第1组）分泌的磷脂酶A2（sPLA2）的活性和花生四烯酸（AA）的产生有关，后者被代谢为前列腺素和血栓烷。这些AA代谢物作用于与G蛋白相连的受体，以诱导PI和PC特异性磷脂酶的活化以及第二信使的产生。静止的LES音与最大程度的PI水解相关，导致次最大水平的肌醇三磷酸（IP3诱导的Ca ++释放，并与DAG相互作用以激活PKC）。在急性食管炎的动物模型中，酸诱导的炎症改变ESO和LES：在LES环形肌中，诱发实验性食管炎后，PI水解的基础水平显着降低，细胞内Ca ++储存功能受损，从而导致静息音降低;细胞内Ca ++释放的减少导致信号传导的转换在正常的LES中，ACh导致Ca ++从细胞内储存释放并激活钙调蛋白依赖性途径;在食管炎后，ACh诱导的收缩取决于细胞外Ca ++的流入，而该作用不足以激活钙调蛋白。 ，而收缩是通过PKC依赖性途径介导的。毒胡萝卜素诱导的Ca ++储存耗竭导致正常LES细胞死亡，这表明可从细胞内储存释放的Ca ++量定义了由最大有效剂量的ACh激活的信号转导途径。

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