Institute En Sante Mentale Of Quebec

Québec, Canada

Institute En Sante Mentale Of Quebec

Québec, Canada
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Chahine M.,Institute En Sante Mentale Of Quebec | Chahine M.,Laval University | O'Leary M.E.,Rowan University
Handbook of Experimental Pharmacology | Year: 2014

The pseudounipolar sensory neurons of the dorsal root ganglia (DRG) give rise to peripheral branches that convert thermal, mechanical, and chemical stimuli into electrical signals that are transmitted via central branches to the spinal cord. These neurons express unique combinations of tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Na+ channels that contribute to the resting membrane potential, action potential threshold, and regulate neuronal firing frequency. The small-diameter neurons (<25 μm) isolated from the DRG represent the cell bodies of C-fiber nociceptors that express both TTX-S and TTX-R Na+ currents. The large-diameter neurons (>35 μm) are typically  low-threshold A-fibers that predominately express TTX-S Na+ currents. Peripheral nerve damage, inflammation, and metabolic diseases alter the expression and function of these Na+ channels leading to increases in neuronal excitability and pain. The Na+ channels expressed in these neurons are the target of intracellular signaling cascades that regulate the trafficking, cell surface expression, and gating properties of these channels. Post-translational regulation of Na+ channels by protein kinases (PKA, PKC, MAPK) alter the expression and function of the channels. Injury-induced changes in these signaling pathways have been linked to sensory neuron hyperexcitability and pain. This review examines the signaling pathways and regulatory mechanisms that modulate the voltage-gated Na+ channels of sensory neurons. © Springer-Verlag Berlin Heidelberg 2014.


Dury A.Y.,Institute En Sante Mentale Of Quebec | Dury A.Y.,Laval University | El Fatimy R.,Institute En Sante Mentale Of Quebec | El Fatimy R.,Laval University | And 7 more authors.
PLoS Genetics | Year: 2013

Fragile X syndrome is caused by loss of function of a single gene encoding the Fragile X Mental Retardation Protein (FMRP). This RNA-binding protein, widely expressed in mammalian tissues, is particularly abundant in neurons and is a component of messenger ribonucleoprotein (mRNP) complexes present within the translational apparatus. The absence of FMRP in neurons is believed to cause translation dysregulation and defects in mRNA transport essential for local protein synthesis and for synaptic development and maturation. A prevalent model posits that FMRP is a nucleocytoplasmic shuttling protein that transports its mRNA targets from the nucleus to the translation machinery. However, it is not known which of the multiple FMRP isoforms, resulting from the numerous alternatively spliced FMR1 transcripts variants, would be involved in such a process. Using a new generation of anti-FMRP antibodies and recombinant expression, we show here that the most commonly expressed human FMRP isoforms (ISO1 and 7) do not localize to the nucleus. Instead, specific FMRP isoforms 6 and 12 (ISO6 and 12), containing a novel C-terminal domain, were the only isoforms that localized to the nuclei in cultured human cells. These isoforms localized to specific p80-coilin and SMN positive structures that were identified as Cajal bodies. The Cajal body localization signal was confined to a 17 amino acid stretch in the C-terminus of human ISO6 and is lacking in a mouse Iso6 variant. As FMRP is an RNA-binding protein, its presence in Cajal bodies suggests additional functions in nuclear post-transcriptional RNA metabolism. Supporting this hypothesis, a missense mutation (I304N), known to alter the KH2-mediated RNA binding properties of FMRP, abolishes the localization of human FMRP ISO6 to Cajal bodies. These findings open unexplored avenues in search for new insights into the pathophysiology of Fragile X Syndrome. © 2013 Dury et al.

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