Inhibition of prostatic smooth muscle contraction by the inhibitor of G protein‐coupled receptor kinase 2/3, CMPD101
Inhibition of prostatic smooth muscle contraction by the inhibitor of G protein‐coupled receptor kinase 2/3, CMPD101
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DOI：
10.1016/j.ejphar.2018.04.022
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发表时间：
2018-07
影响因子：
5
通讯作者：
Qingfeng Yu;C. Gratzke;Yiming Wang;A. Herlemann;F. Strittmatter;B. Rutz;C. Stief;M. Hennenberg
中科院分区：
文献类型：
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作者：
Qingfeng Yu;C. Gratzke;Yiming Wang;A. Herlemann;F. Strittmatter;B. Rutz;C. Stief;M. Hennenberg
α 1-肾上腺素能受体诱导前列腺平滑肌收缩，在良性前列腺增生的病理生理学和下尿路症状的治疗中发挥重要作用。G蛋白偶联受体受翻译后调节，包括G蛋白偶联受体激酶2和3（GRK 2/3）的磷酸化。尽管最近有人提出前列腺中存在翻译后肾上腺素受体调节，但人们对此的了解仍然很少。随着新开发的CMPD 101，一种假定对GRK 2/3具有特异性的小分子抑制剂现已上市。在这里，我们研究了CMPD 101对人前列腺组织平滑肌收缩的影响。电场刺激引起频率依赖性收缩，CMPD 101（5 µM，50 µM）浓度依赖性抑制。50 µM CMPD 101不影响肌球蛋白轻链（MCL）磷酸化或Rho激酶活性，也不改变高摩尔KCl诱导的收缩。去甲肾上腺素、α1-肾上腺素受体激动剂苯肾上腺素、内皮素-1和血栓烷A2类似物U46619诱导浓度依赖性收缩，CMPD 101（50 µM）可抑制这些收缩。CMPD 101（50 µM）未改变β2-肾上腺素受体的磷酸化或前列腺条的β2-肾上腺素能松弛。蛋白质印迹和过氧化物酶染色的分子检测表明GRK 2和GRK 3在人前列腺中表达。荧光双标记证实GRK 2和GRK 3的免疫反应位于前列腺间质中的平滑肌细胞。总之，CMPD 101抑制人前列腺中的肾上腺素能、神经原性和非肾上腺素能平滑肌收缩。潜在的机制可能独立于GRK抑制，以及MLC激酶和Rho激酶的抑制。这可能指向CMPD 101的未知属性。
Alpha1-adrenoceptors induce prostate smooth muscle contraction, and hold a prominent role for pathophysiology and therapy of lower urinary tract symptoms in benign prostatic hyperplasia. G protein-coupled receptors are regulated by posttranslational regulation, including phosphorylation by G protein-coupled receptor kinases 2 and 3 (GRK2/3). Although posttranslational adrenoceptor regulation has been recently suggested to occur in the prostate, this is still marginally understood. With the newly developed CMPD101, a small molecule inhibitor with assumed specificity for GRK2/3 is now available. Here, we studied effects of CMPD101 on smooth muscle contraction of human prostate tissue. Electric field stimulation caused frequency-dependent contractions, which were inhibited concentration-dependently by CMPD101 (5 µM, 50 µM). 50 µM of CMPD101 did not affect myosin light chain (MCL) phosphorylation or Rho kinase activity, and did not alter contractions induced by highmolar KCl. Noradrenaline, the α1-adrenoceptor agonist phenylephrine, endothelin-1, and the thromboxane A2analogue U46619 induced concentration-dependent contractions, which were inhibited by CMPD101 (50 µM). CMPD101 (50 µM) did not change phosphorylation of β2-adrenoceptors or β2-adrenergic relaxation of prostate strips. Molecular detection by Western blot and peroxidase staining suggested expression of GRK2 and GRK3 in human prostates. Double labeling in fluorescence staining confirmed that immunoreactivity for GRK2 and GRK3 was located to smooth muscle cells in the prostate stroma. In conclusion, CMPD101 inhibits adrenergic, neurogenic, and non-adrenergic smooth muscle contractions in the human prostate. Underlying mechanisms may be independent from GRK inhibition, and from inhibition of MLC kinase and Rho kinase. This may point to unknown properties of CMPD101.