Brose Nils, Rosenmund Christian
Abteilung Molekulare Neurobiologie, Max-Planck-Institut für Experimentelle Medizin, D-37075 Göttingen, Germany.
J Cell Sci. 2002 Dec 1;115(Pt 23):4399-411. doi: 10.1242/jcs.00122.
Diacylglycerol is an essential second messenger in mammalian cells. The most prominent intracellular targets of diacylglycerol and of the functionally analogous phorbol esters belong to the protein kinase C (PKC) family. However, at least five alternative types of high-affinity diacylglycerol/phorbol-ester receptor are known: chimaerins, protein kinase D, RasGRPs, Munc13s and DAG kinase gamma. Recent evidence indicates that these have functional roles in diacylglycerol second messenger signalling in vivo and that several cellular processes depend on these targets rather than protein kinase C isozymes. These findings contradict the still prevalent view according to which all diacylglycerol/phorbol-ester effects are caused by the activation of protein kinase C isozymes. RasGRP1 (in Ras/Raf/MEK/ERK signalling) and Munc13-1 (in neurotransmitter secretion) are examples of non-PKC diacylglycerol/phorbol-ester receptors that mediate diacylglycerol and phorbol-ester effects originally thought to be caused by PKC isozymes. In the future, pharmacological studies on PKC must be complemented with alternative experimental approaches to allow the separation of PKC-mediated effects from those caused by alternative targets of the diacylglycerol second messenger pathway. The examples of RasGRP1 and Munc13-1 show that detailed genetic analyses of C(1)-domain-containing non-PKC diacylglycerol/phorbol-ester receptors in mammals are ideally suited to achieve this goal.
二酰甘油是哺乳动物细胞中一种重要的第二信使。二酰甘油以及功能类似的佛波酯在细胞内最主要的作用靶点属于蛋白激酶C（PKC）家族。然而，已知至少还有五种高亲和力的二酰甘油/佛波酯受体：嵌合蛋白、蛋白激酶D、Ras鸟苷酸释放蛋白、Munc13蛋白和二酰甘油激酶γ。最近的证据表明，这些受体在体内二酰甘油第二信使信号传导中发挥功能作用，并且一些细胞过程依赖于这些靶点而非蛋白激酶C同工酶。这些发现与仍然普遍存在的观点相矛盾，即所有二酰甘油/佛波酯的作用都是由蛋白激酶C同工酶的激活所引起的。RasGRP1（在Ras/Raf/MEK/ERK信号传导中）和Munc13-1（在神经递质分泌中）是非PKC二酰甘油/佛波酯受体的例子，它们介导了原本认为是由PKC同工酶引起的二酰甘油和佛波酯的作用。未来，对蛋白激酶C的药理学研究必须辅以其他实验方法，以便将PKC介导的效应与二酰甘油第二信使途径的其他靶点所引起的效应区分开来。RasGRP1和Munc13-1的例子表明，对哺乳动物中含C(1)结构域的非PKC二酰甘油/佛波酯受体进行详细的基因分析非常适合实现这一目标。
