Signal-transduction pathways that regulate smooth muscle function - I. Signal transduction in phasic (esophageal) and tonic (gastroesophageal sphincter) smooth muscles
Signal-transduction pathways that regulate smooth muscle function - I. Signal transduction in phasic (esophageal) and tonic (gastroesophageal sphincter) smooth muscles
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DOI：
10.1152/ajpgi.00398.2004
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发表时间：
2005-03-01
影响因子：
4.5
通讯作者：
Biancani, P
中科院分区：
文献类型：
--
作者：
Harnett, KM;Cao, WB;Biancani, P
食管（Eso）和食管下括约肌（LES）环肌的收缩依赖于不同的信号转导途径。乙酰胆碱诱导的Eso肌收缩与磷脂酰胆碱代谢、甘油二酯和花生四烯酸（AA）的产生以及钙不敏感的PKC β的激活有关。虽然PKC β不需要Ca 2+激活，但需要细胞外Ca 2+的流入或Ca 2+从储存中的释放来激活负责膜磷脂水解和产生第二信使的磷脂酶，其激活PKC β。相比之下，LES使用两种不同的细胞内途径：1）由低剂量激动剂或在维持自发张力期间激活的PKC依赖性途径，以及2）在收缩的初始阶段响应于最大有效剂量的激动剂激活的Ca 2 +-钙调蛋白-肌球蛋白轻链激酶（MLCK）依赖性途径。由激动剂诱导的磷脂酶C活性释放的Ca 2+水平决定了LES中哪种收缩途径被激活。Ca 2 +-钙调素-MLCK依赖性收缩途径在各种平滑肌中已得到很好的表征。然而，对于LES、Eso或其他平滑肌，PKC激活与肌球蛋白轻链（MLC 20）磷酸化和收缩之间的联系步骤尚未明确。此外，在LES环形肌中，低分子量的胰样磷脂酶A2（I组PLA 2）引起AA的产生，AA被代谢为胰高血糖素和血栓素。这些AA代谢物作用于与异源三聚体G蛋白连接的受体，以诱导磷脂酶的活化和第二信使的产生，从而维持LES环形肌的收缩。我们已经研究了由PGF（2 α）和血栓素类似物在初始收缩期激活的信号转导通路，发现这些通路与其他激动剂激活的通路相同。在对低剂量激动剂的反应中或在张力维持期间，可能是由于低水平的钙释放，PKC依赖性途径被激活，而在高剂量的PGF（2 α）和血栓烷类似物下，在收缩的初始阶段，钙调蛋白被激活，PKC活性降低，并且收缩部分地通过Ca 2 +-钙调蛋白-MLCK依赖性途径介导。然而，在持续LES收缩过程中由PGF（2）α和血栓素激活的PKC依赖性信号通路仍有待研究，但初步数据表明，在维持紧张性收缩过程中可能激活一种独特的PKC依赖性通路，这与初始收缩反应期间激活的通路不同。对低水平激动剂的初始收缩反应取决于G（q）的激活。PGF（2 α）引起的持续收缩可能涉及单体G蛋白RhoA的激活，因为收缩被RhoA激酶拮抗剂Y27632抑制。最近在肠平滑肌中报道了初始和持续收缩之间的信号转导途径的这种转变。
Contraction of esophageal (Eso) and lower esophageal sphincter (LES) circular muscle depends on distinct signal-transduction pathways. ACh-induced contraction of Eso muscle is linked to phosphatidylcholine metabolism, production of diacylglycerol and arachidonic acid (AA), and activation of the Ca2+-insensitive PKCepsilon. Although PKCepsilon does not require Ca2+ for activation, either influx of extracellular Ca2+ or release of Ca2+ from stores is needed to activate the phospholipases responsible for hydrolysis of membrane phospholipids and production of second messengers, which activate PKCepsilon. In contrast, the LES uses two distinct intracellular pathways: 1) a PKC-dependent pathway activated by low doses of agonists or during maintenance of spontaneous tone, and 2) a Ca2+-calmodulin-myosin light chain kinase (MLCK)-dependent pathway activated in response to maximally effective doses of agonists during the initial phase of contraction. The Ca2+ levels, released by agonist-induced activity of phospholipase C, determine which contractile pathway is activated in the LES. The Ca2+-calmodulin-MLCK-dependent contractile pathway has been well characterized in a variety of smooth muscles. The steps linking activation of PKC to myosin light chain (MLC20) phosphorylation and contraction, however, have not been clearly defined for LES, Eso, or other smooth muscles. In addition, in LES circular muscle, a low-molecular weight pancreatic-like phospholipase A2 (group I PLA2) causes production of AA, which is metabolized to prostaglandins and thromboxanes. These AA metabolites act on receptors linked to heterotrimeric G proteins to induce activation of phospholipases and production of second messengers to maintain contraction of LES circular muscle. We have examined the signal-transduction pathways activated by PGF(2alpha) and by thromboxane analogs during the initial contractile phase and found that these pathways are the same as those activated by other agonists. In response to low doses of agonists or during maintenance of tone, presumably due to low levels of calcium release, a PKC-dependent pathway is activated, whereas at high doses of PGF(2alpha) and thromboxane analogs, in the initial phase of contraction, calmodulin is activated, PKC activity is reduced, and contraction is mediated, in part, through a Ca2+-calmodulin-MLCK-dependent pathway. The PKC-dependent signaling pathways activated by PGF(2)alpha and by thromboxanes during sustained LES contraction, however, remain to be examined, but preliminary data indicate that a distinct PKC-dependent pathway may be activated during maintenance of tonic contraction, which is different from the one activated during the initial contractile response. The initial contractile response to low levels of agonists depends on activation of G(q). Sustained contraction in response to PGF(2alpha) may involve activation of the monomeric G protein RhoA, because the contraction is inhibited by the RhoA-kinase antagonist Y27632. This shift in signal-transduction pathways between initial and sustained contraction has been recently reported in intestinal smooth muscle.