Integrated regulation of L-type calcium channel Cav1.2 by miR-103 microRNA in neuropathic pain condition
Alexandre
Favereaux1, 2*,
Olivier
Thoumine2, 3,
Rabia
Bouali-Benazzouz1, 2,
Virginie
Roques1, 2,
Guillaume
Drutel2, 4,
Frederic
Nagy1, 2 and
Marc
Landry1, 2
-
1
Neurocentre Magendie Inserm U862, Physiopathologie des reseaux medullaires , France
-
2
Universite de Bordeaux, France
-
3
CNRS UMR 5091 , Physiologie cellulaire de la synapse , France
-
4
Neurocentre Magendie Inserm U862, Physiopathologie de laddiction , France
In chronic pain states, modifications of intrinsic amplification properties of spinal dorsal horn neurons can contribute to central sensitization. These properties rely on L-type calcium channel activation and the associated down-stream genomic up-regulation could sustain long-term sensitization. We previously demonstrated that Cav1.2 calcium channel is specifically up regulated in neuropathic animals (Spinal Nerve Ligation model), and that silencing of Cav1.2 totally reversed the neuropathy-associated mechanical allodynia. The present work aims to decipher mechanisms up-regulating Cav1.2 in neuropathic conditions.
MicroRNAs (miRNAs) are non-coding RNAs that inhibit mRNA translation through mRNA degradation or sequestration. Translation inhibition is achieved by miRNA hybridization with target mRNA according to thermodynamic rules that enable multiple mRNA targeting by a single miRNA. Computer analysis shows that a specific miRNA (miR-103) putatively inhibits the 3 subunits forming the Cav1.2 channel (Cav1.2 alpha1, alpha2-delta1, and beta1 subunits). We performed quantitative PCR on spinal cord samples from neuropathic versus sham animals. We show that in neuropathic animals, a miR-103 down-regulation correlates with an up-regulation of the 3 subunits comprising the Cav1.2 channel. To assess whether an “integrated” silencing actually exists, we designed a luciferase assay where the luciferase gene was fused to the regulation site of each of the 3 subunit mRNA. The results showed that miR-103 indeed inhibits the expression of all three Cav1.2 subunits. Calcium imaging on spinal cord neurons demonstrated that calcium response to depolarizing KCl stimulus was impaired by exogenous miR-103 application. Moreover, in neuropathic animals, intrathecal miR-103 injections partially reversed mechanical allodynia. Thus, we demonstrated that miRNAs play an important role in pain physiopathology through a novel “integrated” silencing mechanism.
Conference:
3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009.
Presentation Type:
Poster Presentation
Citation:
Favereaux
A,
Thoumine
O,
Bouali-Benazzouz
R,
Roques
V,
Drutel
G,
Nagy
F and
Landry
M
(2009). Integrated regulation of L-type calcium channel Cav1.2 by miR-103 microRNA in neuropathic pain condition.
Front. Neurosci.
Conference Abstract:
3rd Mediterranean Conference of Neuroscience .
doi: 10.3389/conf.neuro.01.2009.16.157
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Received:
25 Nov 2009;
Published Online:
25 Nov 2009.
*
Correspondence:
Alexandre Favereaux, Neurocentre Magendie Inserm U862, Physiopathologie des reseaux medullaires, Bordeaux, France, alexandre.favereaux@u-bordeaux.fr