Τίτλος:
Neuronal microRNAs modulate TREK two-pore domain K+ channel expression and current density
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
The TREK family of leak potassium channels has been found to play critical roles in nociception, sensitivity to general anaesthetics, neuroprotection, and memory. The three members of the family, TREK1, TREK2 and TRAAK establish the resting potential and modify the duration, frequency and amplitude of action potentials. Despite their apparent importance, the repertoire of regulatory interactions utilized by cells to control their expression is poorly understood. Herein, the contribution of miRNAs in the regulation of their post-transcriptional gene expression has been examined. Using different assays, miR-124 and to a lesser extent miR-128 and miR-183 were found to reduce TREK1 and TREK2 levels through specific binding to their 3ʹUTRs. In contrast, miR-9 which was predicted to bind to TRAAK 3ʹUTR, did not alter its expression. Expression of miR-124, miR-128 and miR-183 was found to mirror that of Trek1 and Trek2 mRNAs during brain development. Moreover, application of proinflammatory mediators in dorsal root ganglion (DRG) neurons revealed an inverse correlation between miR-124 and Trek1 and Trek2 mRNA expression. Voltage clamp recordings of TREK2-mediated currents showed that miR-124 reduced the sensitivity of TREK2-expressing cells to non-aversive warmth stimulation. Overall, these findings reveal a significant regulatory mechanism by which TREK1 and TREK2 expression and hence activity are controlled in neurons and uncover new druggable targets for analgesia and neuroprotection. Abbreviations: microRNA: miRNA; UTR: untranslated region; K2p channels: two-pore domain K+channels; DRG: dorsal root ganglion; CNS: central nervous system; FBS: fetal bovine serum; TuD: Tough Decoy; TREK: tandem P-domain weak inward rectifying K+ (TWIK)-related K+ channel 1; TRAAK: TWIK-related arachidonic acid K+. © 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group.
Συγγραφείς:
Paschou, M.
Maier, L.
Papazafiri, P.
Selescu, T.
Dedos, S.G.
Babes, A.
Doxakis, E.
Εκδότης:
Taylor and Francis Inc.
Λέξεις-κλειδιά:
microRNA; microRNA 124; microRNA 128; microRNA 183; microRNA 9; nucleotide; potassium channel; potassium channel TRAAK; potassium channel TREK1; potassium channel TREK2; unclassified drug; microRNA; potassium channel protein TREK-1; tandem pore domain potassium channel, 3' untranslated region; adult; animal cell; animal tissue; Article; binding site; controlled study; current density; embryo; gene overexpression; gene targeting; genetic transfection; human; human cell; immunoblotting; male; membrane steady potential; mouse; mRNA expression level; nerve cell; nonhuman; nucleic acid base substitution; potassium current; promoter region; protein expression level; spinal ganglion; voltage clamp technique; animal; cell line; channel gating; cytology; gene expression regulation; genetics; metabolism; nerve cell; reporter gene; RNA interference, 3' Untranslated Regions; Animals; Cell Line; Ganglia, Spinal; Gene Expression Regulation; Genes, Reporter; Humans; Ion Channel Gating; Mice; MicroRNAs; Neurons; Potassium Channels, Tandem Pore Domain; RNA Interference
DOI:
10.1080/15476286.2020.1722450
