Protein kinase C pharmacology: refining the toolbox.
Protein kinase C pharmacology: refining the toolbox.
复制标题
DOI：
10.1042/bj20130220
复制
发表时间：
2013-06-01
期刊：
影响因子：
--
通讯作者：
Newton AC
中科院分区：
文献类型：
--
作者：
Wu-Zhang AX;Newton AC
自从三十年前发现蛋白激酶 C (PKC) 作为促进肿瘤的佛波酯的主要受体以来，它一直备受关注。佛波酯具有激活三类 PKC 同工酶中的两类的强大能力，因此仍然是直接调节 PKC 活性的最佳药理学工具。然而，随着其他佛波酯反应蛋白的发现、各种小分子和肽调节剂的出现以及区分同工酶特异性活性的需要，PKC的药理学变得越来越复杂。毫不奇怪，许多最初被吹捧为 PKC 直接调节剂的化合物随后被证明能够击中许多其他细胞靶标，在某些情况下甚至不直接调节 PKC。 PKC 药理学的复杂性和逆转导致人们对控制 PKC 活性的药理学工具的现状普遍感到困惑。在这里，我们的目的是澄清文献中有关真实和不可信的细胞 PKC 调节剂（包括激活剂、小分子抑制剂和肽）现状的不和谐之处，并解决使用基因编码报告基因和 PKC 突变体来测量这些药物对特定同工酶信号传导时空动态的影响。
Protein kinase C (PKC) has been in the limelight since the discovery three decades ago that it acts as a major receptor for the tumor-promoting phorbol esters. Phorbol esters, with their potent ability to activate two of the three classes of PKC isozymes, have remained the best pharmacological tool for directly modulating PKC activity. However, with the discovery of other phorbol ester-responsive proteins, the advent of various small-molecule and peptide modulators, and the need to distinguish isozyme-specific activity, the pharmacology of PKC has become increasingly complex. Not surprisingly, many of the compounds originally touted as direct modulators of PKC have subsequently been shown to hit many other cellular targets and, in some cases, not even directly modulate PKC. The complexities and reversals in PKC pharmacology have led to widespread confusion about the current status of the pharmacological tools available to control PKC activity. Here, we aim to clarify the cacophony in the literature regarding the current state of bona fide and discredited cellular PKC modulators, including activators, small-molecule inhibitors, and peptides, and also address the use of genetically-encoded reporters and of PKC mutants to measure the effects of these drugs on the spatiotemporal dynamics of signaling by specific isozymes.