Pharmacomechanical coupling: the role of calcium, G-proteins, kinases and phosphatases.
Pharmacomechanical coupling: the role of calcium, G-proteins, kinases and phosphatases.
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DOI：
10.1007/3-540-64753-8_5
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发表时间：
1999
期刊：
影响因子：
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通讯作者：
A. Somlyo;Xuqiong Wu;L. Walker;A. Somlyo
中科院分区：
文献类型：
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作者：
A. Somlyo;Xuqiong Wu;L. Walker;A. Somlyo
30年前引入的药物力学耦合的概念，解释了可以独立于膜电位调节平滑肌收缩的生理机制，已经从一个定义转变为我们现在认为是一个复杂的定义明确的分子机制。众所周知，由化学信使InsP 3从SR释放Ca 2+不是由去极化而是由激动剂-受体相互作用引发的。此外，这种G蛋白偶联的磷脂酰肌醇级联反应是药物力学偶联伞所涵盖的许多过程之一，是复杂和一般信号转导机制的一部分，也在许多非肌肉细胞的不同生物体中运作。同样清楚的是，虽然平滑肌的主要收缩调节机制，MLC 20的磷酸化/去磷酸化是[Ca 2 +]依赖性的，但是激酶和磷酸酶的活性也可以独立于[Ca 2 +]i进行调节。对Ca 2+的敏化作用归因于SMPP-1 M的抑制，这一过程最有可能由单体GTP结合蛋白RhoA的激活主导，RhoA反过来激活Rho激酶，使SMPP-1 M的调节亚基磷酸化并抑制其肌球蛋白磷酸酶活性。这是可能的紧张性阶段的收缩激活的各种兴奋性激动剂是，至少在部分上，介导的Ca 2+敏化机制。对Ca 2+的脱敏可以通过其他激酶抑制MLCK磷酸化或自身磷酸化以及通过环核苷酸激活激酶激活SMPP-1 M（可能涉及磷酸酶激活剂的磷酸化）发生。基于我们目前对细胞中许多相互作用的信号转导机制的复杂性的理解，很可能在未来，我们目前的概念将得到完善，药物力学偶联的其他机制将得到认可，并将确定那些导致病理发生的疾病，如高血压和哮喘。
The concept of pharmacomechanical coupling, introduced 30 years ago to account for physiological mechanisms that can regulate contraction of smooth muscle independently of the membrane potential, has since been transformed from a definition into what we now recognize as a complex of well-defined, molecular mechanisms. The release of Ca2+from the SR by a chemical messenger, InsP3, is well known to be initiated not by depolarization, but by agonist-receptor interaction. Furthermore, this G-protein-coupled phosphatidylinositol cascade, one of many processes covered by the umbrella of pharmacomechanical coupling, is part of complex and general signal transduction mechanisms also operating in many non-muscle cells of diverse organisms. It is also clear that, although the major contractile regulatory mechanism of smooth muscle, phosphorylation/dephosphorylation of MLC20, is [Ca2+]-dependent, the activity of both the kinase and the phosphatase can also be modulated independently of [Ca2+]i. Sensitization to Ca2+is attributed to inhibition of SMPP-1M, a process most likely dominated by activation of the monomeric GTP-binding protein RhoA that, in turn, activates Rho-kinase that phosphorylates the regulatory subunit of SMPP-1M and inhibits its myosin phosphatase activity. It is likely that the tonic phase of contraction activated by a variety of excitatory agonists is, at least in part, mediated by this Ca2+-sensitizing mechanism. Desensitization to Ca2+can occur either through inhibitory phosphorylation of MLCK by other kinases or autophosphorylation and by activation of SMPP-1M by cyclic nucleotide-activated kinases, probably involving phosphorylation of a phosphatase activator. Based on our current understanding of the complexity of the many cross-talking signal transduction mechanisms that operate in cells, it is likely that, in the future, our current concepts will be refined, additional mechanisms of pharmacomechanical coupling will be recognized, and those contributing to the pathologenesis diseases, such as hypertension and asthma, will be identified.