Atypical protein kinase C is a novel mediator of dopamine-enhanced firing in nucleus accumbens neurons
Atypical protein kinase C is a novel mediator of dopamine-enhanced firing in nucleus accumbens neurons
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DOI：
10.1523/jneurosci.3099-04.2005
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发表时间：
2005-01-26
影响因子：
5.3
通讯作者：
Bonci, A
中科院分区：
文献类型：
--
作者：
Hopf, FW;Mailliard, WS;Bonci, A
目前的概念认为伏隔核（NAcb）多巴胺介导了几种动机和成瘾行为。虽然蛋白激酶A （PKA）与多巴胺和环腺苷3 ‘,5 ’单磷酸调节的磷酸化蛋白32 kDa在NAcb多巴胺受体通量中的作用已被广泛研究，但蛋白激酶C （PKC）对NAcb放电的贡献知之甚少。本研究表明，PKC抑制剂双吲哚酰马来酰亚胺可以阻止多巴胺介导的nab壳介质棘神经元的spike放电增强，而磷脂酶C抑制剂1-[6-（（17b- 3-甲氧基- 1,3,5(10)-三烯- 17-基）氨基）己基]- 1H-吡罗- 2,5-二酮则不能，这表明非典型PKC （aPKC）非二酰基甘油异构体起作用。在这方面，多巴胺对放电的调节可以通过aPKCs的假底物肽抑制剂的细胞内灌注来阻止。我们还提供证据，使用体外激酶测定，多巴胺受体激活增加纹状体膜aPKC活性。最后，用forskolin直接激活PKA，即使在抑制aPKCs的过程中，也会增强放电，这表明aPKCs在PKA激活的上游起作用。因此，aPKCs似乎介导了NAcb壳中多巴胺能的增强，因此可能在NAcb和多巴胺依赖的目标导向行为中发挥关键作用。
Current concepts suggest that nucleus accumbens ( NAcb) dopamine mediates several motivated and addictive behaviors. Although the role of protein kinase A ( PKA) and dopamine and cyclic adenosine 3 ', 5 ' monophosphate- regulated phosphoprotein 32 kDa in NAcb dopamine receptor throughput has been studied extensively, the contribution of protein kinase C ( PKC) to NAcb firing is poorly understood. Here we show that dopamine- mediated enhancement of spike firing in NAcb shell medium spiny neurons was prevented by the PKC inhibitor bisindolylmaleimide but not by the phospholipase C inhibitor 1-[ 6-(( 17b- 3- methoxyestra- 1,3,5( 10)- trien- 17- yl) amino) hexyl]- 1H- pyrrole- 2,5- dione, suggesting a role for a diacylglycerol- independent atypical PKC ( aPKC) isoform. In this regard, modulation of firing by dopamine was prevented by intracellular perfusion of a pseudosubstrate peptide inhibitor for aPKCs. We also provide evidence, using an in vitro kinase assay, that dopamine receptor activation increased aPKC activity in striatal membranes. Finally, direct activation of PKA with forskolin enhanced firing even during inhibition of aPKCs, suggesting that aPKCs acted upstream of PKA activation. Thus, aPKCs appear to mediate dopaminergic enhancement of spike firing in the NAcb shell, and may therefore play a critical role in NAcb- and dopamine- dependent goal- directed behaviors.