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

Abstract

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.