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Splicing and Dicing Alcohol Responsiveness

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Science Signaling  05 Aug 2008:
Vol. 1, Issue 31, pp. ec277
DOI: 10.1126/scisignal.131ec277

The activity of BK channels, which are large-conductance K+ channels, is potentiated by alcohol; however, the channel rapidly becomes tolerant or less sensitive to alcohol (see Levitan). BK channels are encoded by the KCNMA1 gene, which undergoes alternative splicing to produce transcripts with specific exons, and some of these confer specific regulatory properties to the channels. For example, the abundance of transcripts that include STREX (stress axis-regulated exon) is increased by stress hormones, such as adrenocorticotropic hormone, and this produces a channel that is regulated by protein kinase A. Pietrzykowski et al. found that in regions of the brain responsive to ethanol, there were eight BK channel transcripts, and only two of these were present after exposure to ethanol. Five of the six transcripts that were diminished after exposure to ethanol included exon 29, and neither of the remaining two included exon 29, leading the authors to name this exon ALCOREX (alcohol-regulated exon). Of the remaining two transcripts, one included STREX and one lacked STREX and was called INSERTLESS. Using bioinformatics tools, the authors searched the 3′ untranslated region (3′-UTR) of the BK transcript for sequences that matched a library of known rodent neuronal microRNAs (miRNAs) and identified a miR-9 target sequence. Single-neuron transcript analysis indicated that miR-9 was present in neurons responsive to ethanol and that ethanol exposure increased the abundance of this miRNA. Analysis of the BK channel transcript from brain tissue revealed that there were three 3′-UTR variants and that only one of these (3′UTR-2.2) contained the miR-9 target sequence. The abundance of 3′UTR-2.2 transcripts was decreased after ethanol exposure, and transcripts containing ALCOREX had this miR-9-responsive 3′-UTR, whereas STREX-containing transcripts had either the miR-9-responsive 3′-UTR or a nonresponsive 3′-UTR. Heterologous expression of STREX, ALCOREX, or INSERTLESS BK transcripts showed that the channels produced from the ALCOREX-containing transcripts showed the greatest potentiation by ethanol, with INSERTLESS channels showing less potentiation, whereas those produced from STREX-containing transcripts were not responsive to ethanol. Computational modeling that included information about transcript abundance and the known or predicted electrophysiological properties of the assembled channels allowed the authors to predict that alcohol led to a drop in the abundance of ALCOREX-INSERTLESS heteromeric channels and a concomitant increase in STREX-INSERTLESS heteromeric channels, which would produce cells with only 15% of the original responsiveness to alcohol. Searching sequences that may also be regulated by miR-9 suggests that this mechanism may be important for several other targets relevant to alcohol responsiveness.

A. Z. Pietrzykowski, R. M. Friesen, G. E. Martin, S. I. Puig, C. L. Nowak, P. M. Wynne, H. T. Siegelmann, S. N. Treistman, Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol. Neuron 59, 274-287 (2008). [PubMed]

I. B. Levitan, miXED messages in ion channel modulation. Neuron 59, 188-189 (2008). [PubMed]

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