A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons

Abstract

Neuropathic pain is a refractory disease characterized by maladaptive changes in gene transcription and translation within the sensory pathway. Long noncoding RNAs (lncRNAs) are emerging as new players in gene regulation, but how lncRNAs operate in the development of neuropathic pain is unclear. Here we identify a conserved lncRNA for Kcna2 (named Kcna2 antisense RNA) in first-order sensory neurons of rat dorsal root ganglion (DRG). Peripheral nerve injury increases Kcna2 antisense RNA expression in injured DRG through activation of myeloid zinc finger protein 1, a transcription factor that binds to Kcna2 antisense RNA gene promoter. Mimicking this increase downregulates Kcna2, reduces total Kv current, increases excitability in DRG neurons, and produces neuropathic pain symptoms. Blocking this increase reverses nerve injury-induced downregulation of DRG Kcna2 and attenuates development and maintenance of neuropathic pain. These findings suggest native Kcna2 antisense RNA as a new therapeutic target for the treatment of neuropathic pain.

Long Noncoding RNA Kcna2 Antisense RNA Contributes to Ventricular Arrhythmias via Silencing Kcna2 in Rats With Congestive Heart Failure

“…We previously identified the expression of Kcna2 AS in the dorsal root ganglion of several species, including rats, mice, monkeys, and humans 17. Herein, we also detected this transcript in the cardiac myocytes and fibroblasts of rats (Figure S2B).…”

“…Interestingly, Kcna2 AS knockdown also ameliorated heart failure–induced decreases in Kcna2 mRNA and protein expression. Increases in endogenous Kcna2 AS expression have been shown to be induced by the overexpression of the myeloid zinc finger protein 1 (MZF1), a transcriptional activator, via specific and selective binding to the Kcna2 AS promoter 17, 21. In addition, MZF1 can inhibit cardiac cell differentiation through the activation of the Nkx2.5 cardiac enhancer during embryonic heart development.…”

“…RNA was reverse transcribed using the ThermoScript reverse transcriptase with strand‐specific reverse transcription primers targeting the unique sequences for KCNA or Kcna2 AS RNA (Figure S2A). RT and PCR primers listed in Table S1 were determined from the University of California, Santa Cruz, genome database and our previous studies 17, 21. Template (1 μL) was amplified by PCR with TaKaRa Taq DNA polymerase (Clontech Laboratories, Inc) in 20 μL total reaction volume containing 0.5 μmol/L of PCR primer.…”

It is an RNA world

“…In rats, the lncRNA is upregulated in neurons in response to damage. 6 Although the lncRNA is expressed in humans, its relationship to KCNA2 and the mechanism by which it regulates gene expression still need to be determined before it can be considered a therapeutic target. 7 Also in 2013, a team from the University of California, San Diego and The University of Texas MD Anderson Cancer Center reported two lncRNA targets that functionally contribute to prostate cancer growth.…”

Altered myocardial gene expression profiling in the ischemic tissues at different time points after cardiac ischemia/reperfusion in rats

“…Recently, long non-coding RNAs (lncRNAs) have become an increased research focus that plays critical roles in many biological processes [15][16][17][18][19][20]. Recent studies suggest that lncRNAs are often accompanied by important regulatory functions in the heart [21][22][23].…”