Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol

被引：284

作者：

Pietrzykowski, Andrzej Z. ^{[1
]}

Friesen, Ryan M. ^{[1
]}

Martin, Gilles E. ^{[1
]}

Puig, Sylvie I. ^{[1
]}

Nowak, Cheryl L. ^{[1
]}

Wynne, Patricia M. ^{[1
]}

Siegelmann, Hava T. ^{[2
]}

Treistman, Steven N. ^{[1
]}

机构：

[1] Univ Massachusetts, Sch Med, Brudnick Neuropsychiat Res Inst, Dept Psychiat, Worcester, MA 01604 USA

[2] Univ Massachusetts, Biologically Inspired Neural & Dynam Syst Lab, Dept Comp Sci, Amherst, MA 01003 USA

来源：

NEURON | 2008年 / 59卷 / 02期

关键词：

D O I：

10.1016/j.neuron.2008.05.032

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Tolerance represents a critical component of addiction. The large-conductance calcium- and voltage-activated potassium channel (BK) is a well-established alcohol target, and an important element in behavioral and molecular alcohol tolerance. We tested whether microRNA, a newly discovered class of gene expression regulators, plays a role in the development of tolerance. We show that in adult mammalian brain, alcohol upregulates microRNA miR-9 and mediates posttranscriptional reorganization in BK mRNA splice variants by miR-9-dependent destabilization of BK mRNAs containing 3 ' UTRs with a miR-9 Recognition Element (MRE). Different splice variants encode BK isoforms with different alcohol sensitivities. Computational modeling indicates that this miR-9-dependent mechanism contributes to alcohol tolerance. Moreover, this mechanism can be extended to include regulation of additional miR-9 targets relevant to alcohol abuse. Our results describe a mechanism of multiplex regulation of stability of alternatively spliced mRNA by microRNA in drug adaptation and neuronal plasticity.

引用

页码：274 / 287

页数：14

共 80 条

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