Kalrn promoter usage and isoform expression respond to chronic cocaine exposure.
Kalrn promoter usage and isoform expression respond to chronic cocaine exposure.
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DOI：
10.1186/1471-2202-12-20
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发表时间：
2011-02-17
期刊：
影响因子：
2.4
通讯作者：
Eipper BA
中科院分区：
文献类型：
--
作者：
Mains RE;Kiraly DD;Eipper-Mains JE;Ma XM;Eipper BA
可卡因对行为的长期影响伴随着纹状体中棘神经元兴奋性谷氨酸能突触的结构变化。Kalrn基因编码几种不同的功能异构体；这些多结构域鸟嘌呤核苷酸交换因子(GEF)包含已知的与磷脂酰肌醇以及许多不同蛋白质相互作用的额外结构域。不同的Kalirin亚型通过激活Rho蛋白和与其他蛋白的相互作用影响细胞骨架组织。成年雄性啮齿动物长期接触可卡因会增加纹状体中Kalirin 7的水平。当长期接触可卡因时，缺乏Kalirin 7(主要成体亚型)的小鼠无法显示伏隔核中树突棘密度的增加，对可卡因的位置偏好减弱，并表现出对可卡因反应增加的运动活动。用实时定量聚合酶链式反应研究了小鼠Kalrn基因的交替启动子和3‘端外显子的使用。虽然最远端的两个全长Kalrn启动子在前额叶皮质中使用相同，但这些启动子中较近的一个占伏隔核表达的大部分转录本。Kalirin 7亚型特有的3‘末端外显子在前额叶皮质的Kalrn转录本中所占的比例比在伏核中所占的比例更大。蛋白质印迹分析证实了这些差异。慢性可卡因治疗增加了编码Δ-Kalirin异构体的启动子的使用，但不改变全长Kalirin启动子的使用。慢性可卡因暴露后，Kalirin 7特有的3‘末端外显子的使用量增加。Kalrn启动子和3‘端外显子的利用具有区域特异性。在伏隔核中，可卡因介导的启动子使用和3‘端外显子使用的改变有利于Kalirin7和Δ-Kalirin7的表达。Δ-异构体缺乏Sec14p结构域和全长Kalirin亚型中发现的九个类幽灵蛋白重复序列中的四个，增加了脊柱头部，而不增加树突棘数量。因此，可卡因介导的Kalrn基因选择性剪接的变化可能对观察到的行为、形态和生化反应有重要贡献。
The long-term effects of cocaine on behavior are accompanied by structural changes in excitatory glutamatergic synapses onto the medium spiny neurons of the striatum. The Kalrn gene encodes several functionally distinct isoforms; these multidomain guanine nucleotide exchange factors (GEFs) contain additional domains known to interact with phosphatidylinositides as well as with a number of different proteins. Through their activation of Rho proteins and their interactions with other proteins, the different Kalirin isoforms affect cytoskeletal organization. Chronic exposure of adult male rodents to cocaine increases levels of Kalirin 7 in the striatum. When exposed chronically to cocaine, mice lacking Kalirin 7, the major adult isoform, fail to show an increase in dendritic spine density in the nucleus accumbens, show diminished place preference for cocaine, and exhibit increased locomotor activity in response to cocaine. The use of alternate promoters and 3'-terminal exons of the mouse Kalrn gene were investigated using real-time quantitative polymerase chain reaction. While the two most distal full-length Kalrn promoters are used equally in the prefrontal cortex, the more proximal of these promoters accounts for most of the transcripts expressed in the nucleus accumbens. The 3'-terminal exon unique to the Kalirin 7 isoform accounts for a greater percentage of the Kalrn transcripts in prefrontal cortex than in nucleus accumbens. Western blot analyses confirmed these differences. Chronic cocaine treatment increases usage of the promoter encoding the Δ-Kalirin isoforms but does not alter full-length Kalirin promoter usage. Usage of the 3'-terminal exon unique to Kalirin 7 increases following chronic cocaine exposure. Kalrn promoter and 3'-terminal exon utilization are region-specific. In the nucleus accumbens, cocaine-mediated alterations in promoter usage and 3'-terminal exon usage favor expression of Kalirin 7 and Δ-Kalirin 7. The Δ-isoform, which lacks a Sec14p domain and four of the nine spectrin-like repeats found in full-length Kalirin isoforms, increases spine headsize without increasing dendritic spine numbers. Thus cocaine-mediated changes in alternative splicing of the Kalrn gene may contribute importantly to the behavioral, morphological and biochemical responses observed.
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影响因子：
11
作者：
Hill, J. J.;Hashimoto, T.;Lewis, D. A.
通讯作者：
Lewis, D. A.
DOI：
10.1073/pnas.1009874107
发表时间：
2010-08-17
影响因子：
11.1
作者：
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通讯作者：
Greengard, Paul
DOI：
10.1073/pnas.0904636106
发表时间：
2009-08-04
影响因子：
11.1
作者：
Cahill, Michael E.;Xie, Zhong;Penzes, Peter
通讯作者：
Penzes, Peter
影响因子：
4.4
作者：
Beresewicz, Malgorzata;Kowalczyk, Joanna E.;Zablocka, Barbara
通讯作者：
Zablocka, Barbara
影响因子：
3.6
作者：
Hwang, Cheol Kyu;Kim, Chun Sung;Loh, Horace H.
通讯作者：
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