Regulation of Nitric Oxide–Sensitive Guanylyl Cyclase Cyclic GMP Phosphodiesterases and Regulation of Smooth Muscle Function Structure, Regulation, and Function of Membrane Guanylyl Cyclase Receptors, With a Focus on GC-A Cyclic GMP–Dependent Protein Kinases and the Cardiovascular System: Insights F
Regulation of Nitric Oxide–Sensitive Guanylyl Cyclase Cyclic GMP Phosphodiesterases and Regulation of Smooth Muscle Function Structure, Regulation, and Function of Membrane Guanylyl Cyclase Receptors, With a Focus on GC-A Cyclic GMP–Dependent Protein Kinases and the Cardiovascular System: Insights F
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发表时间：
2003
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通讯作者：
S. Rybalkin;C. Yan;K. Bornfeldt;J. Beavo
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作者：
S. Rybalkin;C. Yan;K. Bornfeldt;J. Beavo
响应于心房利钠肽（ANP）或一氧化氮（NO）产生的环GMP（cGMP）是平滑肌张力的短期变化和对慢性药物治疗或增殖信号的长期响应的重要调节剂。平滑肌细胞（SMC）利用磷酸二酯酶（PDE）同工酶的不同组合的能力允许cGMP介导这些多个过程。例如，PDE 5作为主要cGMP水解PDE有效地控制平滑肌松弛的发展。为了发生收缩，PDE 5被激活，cGMP福尔斯下降。相反，PDE 5活性的阻断允许舒张周期延长和增强。最近显示的cGMP结合GAF A结构域直接激活PDE 5表明，该调节位点可能是新药开发的靶点。与血管收缩剂引发的收缩相关的钙激增也会激活钙/钙调蛋白依赖性PDE（PDE 1A）。PDE 5和PDE 1A共同降低cGMP足以使收缩。长期而言，PDE 5和PDE 1A mRNA均由鸟苷酸环化酶的慢性刺激诱导。这种诱导是对NO释放药物产生耐受性的主要原因。最后，高水平的cGMP或cAMP也起到制动器的作用，以减弱SMC对许多有丝分裂原的增殖反应。血管损伤后，为了使SMC增殖，cGMP和cAMP的水平必须降低。在人类中，这种减少在很大程度上是由另一种钙/钙调素依赖性PDE（PDE 1C）的诱导引起的，该PDE允许制动被释放并开始增殖。(Circ Res. 2003;93：280-291）。
Cyclic GMP (cGMP) made in response to atrial natriuretic peptide (ANP) or nitric oxide (NO) is an important regulator of short-term changes in smooth muscle tone and longer-term responses to chronic drug treatment or proliferative signals. The ability of smooth muscle cells (SMCs) to utilize different combinations of phosphodiesterase (PDE) isozymes allows cGMP to mediate these multiple processes. For example, PDE5 as a major cGMP-hydrolyzing PDE effectively controls the development of smooth muscle relaxation. In order for contraction to occur, PDE5 is activated and cGMP falls. Conversely, blockade of PDE5 activity allows the relaxation cycle to be prolonged and enhanced. A recently shown direct activation of PDE5 by cGMP binding to the GAF A domain suggests that this regulatory site might be a target for new drug development. The calcium surge associated with vasoconstrictor initiated contraction also activates a calcium/calmodulin-dependent PDE (PDE1A). Together, PDE5 and PDE1A lower cGMP sufficiently to allow contraction. Longer term, both PDE5 and PDE1A mRNA are induced by chronic stimulation of guanylyl cyclase. This induction is a major cause of the tolerance that develops to NO-releasing drugs. Finally, high levels of cGMP or cAMP also act as a brake to attenuate the proliferative response of SMCs to many mitogens. After vessel damage, in order for SMC proliferation to occur, the levels of cGMP and cAMP must be decreased. In humans, this decrease is caused in large part by induction of another Ca /calmodulin-dependent PDE (PDE1C) that allows the brake to be released and proliferation to start. (Circ Res. 2003;93:280-291.)