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

Neuron. 2008 Jul 31;59(2):274-87. doi: 10.1016/j.neuron.2008.05.032.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / drug effects*
  • Adaptation, Physiological / genetics
  • Animals
  • Animals, Newborn
  • Cell Line
  • Cells, Cultured
  • Ethanol / pharmacology*
  • Humans
  • Large-Conductance Calcium-Activated Potassium Channels / genetics
  • Large-Conductance Calcium-Activated Potassium Channels / metabolism*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neurons / drug effects
  • Neurons / physiology*
  • Protein Processing, Post-Translational / drug effects
  • Protein Processing, Post-Translational / physiology*
  • RNA Splicing / physiology*
  • RNA Stability / physiology*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Large-Conductance Calcium-Activated Potassium Channels
  • MicroRNAs
  • Ethanol