Kazanietz M G, Caloca M J, Eroles P, Fujii T, García-Bermejo M L, Reilly M, Wang H
Center for Experimental Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, 19104-6160, USA.
Biochem Pharmacol. 2000 Nov 15;60(10):1417-24. doi: 10.1016/s0006-2952(00)00470-6.
The phorbol ester tumor promoters and related analogs are widely used as potent activators of protein kinase C (PKC). The phorbol esters mimic the action of the lipid second messenger diacylglycerol (DAG). The aim of this commentary is to highlight a series of important and controversial concepts in the pharmacology and regulation of phorbol ester receptors. First, phorbol ester analogs have marked differences in their biological properties. This may be related to a differential regulation of PKC isozymes by distinct analogs. Moreover, it seems that marked differences exist in the ligand recognition properties of the C1 domains, the phorbol ester/DAG binding sites in PKC isozymes. Second, an emerging theme that we discuss here is that phorbol esters also target receptors unrelated to PKC isozymes, a concept that has been largely ignored. These novel receptors lacking kinase activity include chimaerins (a family of Rac-GTPase-activating proteins), RasGRP (a Ras exchange factor), and Unc-13/Munc-13 (a family of proteins involved in exocytosis). Unlike the classical and novel PKCs, these "non-kinase" phorbol ester receptors possess a single copy of the C1 domain. Interestingly, each receptor class has unique pharmacological properties and biochemical regulation. Lastly, it is well established that phorbol esters and related analogs can translocate each receptor to different intracellular compartments. The differential pharmacological properties of the phorbol ester receptors can be exploited to generate specific agonists and antagonists that will be helpful tools to dissect their cellular function.
佛波酯肿瘤促进剂及相关类似物被广泛用作蛋白激酶C（PKC）的强效激活剂。佛波酯可模拟脂质第二信使二酰基甘油（DAG）的作用。本述评的目的是强调佛波酯受体药理学及调节方面的一系列重要且有争议的概念。首先，佛波酯类似物在生物学特性上存在显著差异。这可能与不同类似物对PKC同工酶的差异调节有关。此外，PKC同工酶中佛波酯/DAG结合位点即C1结构域的配体识别特性似乎也存在显著差异。其次，我们在此讨论的一个新出现的主题是，佛波酯还靶向与PKC同工酶无关的受体，这一概念在很大程度上被忽视了。这些缺乏激酶活性的新型受体包括嵌合蛋白（一类Rac - GTP酶激活蛋白）、RasGRP（一种Ras交换因子）和Unc - 13/Munc - 13（一类参与胞吐作用的蛋白）。与经典和新型PKC不同，这些“非激酶”佛波酯受体仅含有一个C1结构域拷贝。有趣的是，每类受体都具有独特的药理学特性和生化调节机制。最后，佛波酯及相关类似物能将每种受体转运至不同的细胞内区室，这一点已得到充分证实。可利用佛波酯受体的不同药理学特性来开发特异性激动剂和拮抗剂，这将有助于剖析它们的细胞功能。
