3 ms·

The author seems confused about how BK channels relate to tolerance, here he notes that decreased BK channels lead to increased tolerance: "Exposure to alcohol

The author seems confused about how BK channels relate to tolerance, here he notes that decreased BK channels lead to increased tolerance: "Exposure to alcohol upregulates microRNA (mir-9), which in turn modifies BK mRNA, selectively destabilizing certain types of BK mRNA." Then later he seems to be stating that decreased BK channels would lead to decreased tolerance: "The consequence of this would then be that the development of alcohol tolerance could be slowed or halted by preventing the modification of BK channels, like by using RNAi to degrade certain types of BK mRNA." Perhaps he meant "by using RNAi to degrade mir-9". Ignoring the above issues, it seems very hand wavy to say "let's just get this RNA interfering drug into your brain and target this specific BK RNA".

100ideas 5y ago
The author referenced a paper from 2009 about the microRNAs and BK subunits: "Post-transcriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714263/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714263/ "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 post-transcriptional 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 regulation of additional miR-9 targets relevant to alcohol abuse. Our results describe a novel mechanism of multiplex regulation of stability of alternatively spliced mRNA by miRNA in drug adaptation and neuronal plasticity."

100ideas 5y ago

The author referenced a paper from 2009 about the microRNAs and BK subunits: "Post-transcriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714263/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714263/ "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 post-transcriptional 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 regulation of additional miR-9 targets relevant to alcohol abuse. Our results describe a novel mechanism of multiplex regulation of stability of alternatively spliced mRNA by miRNA in drug adaptation and neuronal plasticity."