Modulation of BK channel by MicroRNA-9 in neurons after exposure to HIV and methamphetamine.

TitleModulation of BK channel by MicroRNA-9 in neurons after exposure to HIV and methamphetamine.
Publication TypeJournal Article
Year of Publication2013
AuthorsTatro, ET, Hefler, S, Shumaker-Armstrong, S, Soontornniyomkij, B, Yang, M, Yermanos, A, Wren, N, Moore, DJ, Achim, C
JournalJ Neuroimmune Pharmacol
Volume8
Issue5
Pagination1210-23
Date Published2013 Dec
ISSN1557-1904
KeywordsAdult, AIDS Dementia Complex, Autopsy, Case-Control Studies, Cell Line, Central Nervous System Stimulants, Female, Gene Expression Regulation, Humans, In Situ Hybridization, Large-Conductance Calcium-Activated Potassium Channel alpha Subunits, Male, Methamphetamine, MicroRNAs, Neurons, Protein Isoforms, Retrospective Studies, Reverse Transcriptase Polymerase Chain Reaction, Young Adult
Abstract

MicroRNAs (miR) regulate phenotype and function of neurons by binding to miR-response elements (MRE) in the 3' untranslated regions (3'UTR) of various messenger RNAs to inhibit translation. MiR expression can be induced or inhibited by environmental factors like drug exposure and viral infection, leading to changes in cellular physiology. We hypothesized that the effects of methamphetamine (MA) and human immunodeficiency virus (HIV)-infection in the brain will induce changes in miR expression, and have downstream regulatory consequences in neurons. We first used a PCR-based array to screen for differential expression of 380 miRs in frontal cortex autopsy tissues of HIV-positive MA abusers and matched controls. These results showed significantly increased expression of the neuron-specific miR-9. In vitro, we used SH-SY5Y cells, an experimental system for dopaminergic studies, to determine miR expression by quantitative PCR after exposure to MA in the presence or absence of conditioned media from HIV-infected macrophages. Again, we found that miR-9 was significantly increased compared to controls. We also examined the inwardly rectifying potassium channel, KCNMA1, which has alternative splice variants that contain an MRE to miR-9. We identified alternate 3'UTRs of KCNMA1 both in vitro and in the autopsy specimens and found differential splice variant expression of KCNMA1, operating via the increased miR-9. Our results suggest that HIV and MA -induced elevated miR-9, leading to suppression of MRE-containing splice variants of KCNMA1, which may affect neurotransmitter release in dopaminergic neurons.

DOI10.1007/s11481-013-9446-8
Alternate JournalJ Neuroimmune Pharmacol
PubMed ID23508624
PubMed Central IDPMC3715589
Grant ListAI36214 / AI / NIAID NIH HHS / United States
DA026306 / DA / NIDA NIH HHS / United States
DA031591 / DA / NIDA NIH HHS / United States
MH083506 / MH / NIMH NIH HHS / United States
P30 MH062512 / MH / NIMH NIH HHS / United States
P30MH062512 / MH / NIMH NIH HHS / United States
P50 DA026306 / DA / NIDA NIH HHS / United States
R03 DA031591 / DA / NIDA NIH HHS / United States
U01 MH083506 / MH / NIMH NIH HHS / United States
U19 AI096113 / AI / NIAID NIH HHS / United States
U24 MH100928 / MH / NIMH NIH HHS / United States