Up-regulation of Cavß3 subunit in primary sensory neurons increases voltage-activated Ca2+ channel activity and nociceptive input in neuropathic pain.

Authors: Li, Li  Cao, Xue-Hong  Chen, Shao-Rui  Han, Hee-Dong  Lopez-Berestein, Gabriel  Sood, Anil K  Pan, Hui-Lin 
Citation: Li L, etal., J Biol Chem. 2012 Feb 17;287(8):6002-13. doi: 10.1074/jbc.M111.310110. Epub 2011 Dec 20.
Pubmed: (View Article at PubMed) PMID:22187436
DOI: Full-text: DOI:10.1074/jbc.M111.310110

High voltage-activated calcium channels (HVACCs) are essential for synaptic and nociceptive transmission. Although blocking HVACCs can effectively reduce pain, this treatment strategy is associated with intolerable adverse effects. Neuronal HVACCs are typically composed of α(1), ß (Cavß), and α(2)d subunits. The Cavß subunit plays a crucial role in the membrane expression and gating properties of the pore-forming α(1) subunit. However, little is known about how nerve injury affects the expression and function of Cavß subunits in primary sensory neurons. In this study, we found that Cavß(3) and Cavß(4) are the most prominent subtypes expressed in the rat dorsal root ganglion (DRG) and dorsal spinal cord. Spinal nerve ligation (SNL) in rats significantly increased mRNA and protein levels of the Cavß(3), but not Cavß(4), subunit in the DRG. SNL also significantly increased HVACC currents in small DRG neurons and monosynaptic excitatory postsynaptic currents of spinal dorsal horn neurons evoked from the dorsal root. Intrathecal injection of Cavß(3)-specific siRNA significantly reduced HVACC currents in small DRG neurons and the amplitude of monosynaptic excitatory postsynaptic currents of dorsal horn neurons in SNL rats. Furthermore, intrathecal treatment with Cavß(3)-specific siRNA normalized mechanical hyperalgesia and tactile allodynia caused by SNL but had no significant effect on the normal nociceptive threshold. Our findings provide novel evidence that increased expression of the Cavß(3) subunit augments HVACC activity in primary sensory neurons and nociceptive input to dorsal horn neurons in neuropathic pain. Targeting the Cavß(3) subunit at the spinal level represents an effective strategy for treating neuropathic pain.

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CRRD ID: 13514092
Created: 2018-03-28
Species: All species
Last Modified: 2018-03-28
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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.