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PMID: 18667155 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Neuron ·Vol. 59 ·No. 2 ·2008-07-31 ·Pages 274-87

Pietrzykowski AZ, Friesen RM, Martin GE, Puig SI, Nowak CL, Wynne PM, Siegelmann HT, Treistman SN

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.

MeSH Terms
Adaptation, Physiological/drug effects,genetics Animals Animals, Newborn Cell Line Cells, Cultured Ethanol/pharmacology Humans Large-Conductance Calcium-Activated Potassium Channels/genetics,metabolism MicroRNAs/genetics,metabolism Neurons/drug effects,physiology Protein Processing, Post-Translational/drug effects,physiology RNA Splicing/physiology RNA Stability/physiology Rats Rats, Sprague-Dawley
Chemicals
Large-Conductance Calcium-Activated Potassium Channels MicroRNAs Ethanol
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Pietrzykowski Andrzej Z
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, 303 Belmont Street, Worcester, MA 01604, USA.
Friesen Ryan M
Martin Gilles E
Puig Sylvie I
Nowak Cheryl L
Wynne Patricia M
Siegelmann Hava T
Treistman Steven N
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Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
1097-4199
DOI
10.1016/j.neuron.2008.05.032
Published
2008-07-31
Pages
274-87
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC2714263
Subset
IM
Grants
NIAAA NIH HHS · R01 AA018038-02 · United States
NIAAA NIH HHS · R01 AA018038 · United States
NIAAA NIH HHS · AA08003 · United States
NIAAA NIH HHS · R01 AA008003-21 · United States
NIAAA NIH HHS · R01 AA008003 · United States
Corrections
CommentIn
PMID: 18667146
External Links
PubMed source DOI: 10.1016/j.neuron.2008.05.032 PMC Full Text View journal details
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