Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol
Brudnick Neuropsychiatric Research Institute, Department of Psychiatry; Treistman Lab; Graduate School of Biomedical Sciences, Neuroscience Program; Martin Lab
Adaptation, Physiological; Animals; Animals, Newborn; Cell Line; Cells, Cultured; Ethanol; Humans; Large-Conductance Calcium-Activated Potassium; Channels; MicroRNAs; Neurons; Protein Processing, Post-Translational; RNA Splicing; RNA Stability; Rats; Rats, Sprague-Dawley
Neuroscience and Neurobiology
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.
DOI of Published Version
Neuron. 2008 Jul 31;59(2):274-87. Link to article on publisher's site
Pietrzykowski AZ, Friesen RM, Martin GE, Puig SI, Nowak CL, Wynne PM, Siegelmann HT, Treistman SN. (2008). Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol. Open Access Articles. https://doi.org/10.1016/j.neuron.2008.05.032. Retrieved from https://escholarship.umassmed.edu/oapubs/2013