Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol.
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.
Pietrzykowski
Andrzej Z
AZ
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, 303 Belmont Street, Worcester, MA 01604, USA.
Friesen
Ryan M
RM
Martin
Gilles E
GE
Puig
Sylvie I
SI
Nowak
Cheryl L
CL
Wynne
Patricia M
PM
Siegelmann
Hava T
HT
Treistman
Steven N
SN
D000222:Adaptation, Physiological / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D002478:Cells, Cultured; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D012326:RNA Splicing / Q000502:physiology*; D020871:RNA Stability / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D051036:Large-Conductance Calcium-Activated Potassium Channels; D035683:MicroRNAs; D000431:Ethanol