β3, a novel auxiliary subunit for the voltage‐gated sodium channel, is expressed preferentially in sensory neurons and is upregulated in the chronic constriction injury model of neuropathic pain

Abstract

Adult dorsal root ganglia (DRG) have been shown to express a wide range of voltage-gated sodium channel alpha-subunits. However, of the auxiliary subunits, beta1 is expressed preferentially in only large- and medium-diameter neurons of the DRG while beta2 is absent in all DRG cells. In view of this, we have compared the distribution of beta1 in rat DRG and spinal cord with a novel, recently cloned beta1-like subunit, beta3. In situ hybridization studies demonstrated high levels of beta3 mRNA in small-diameter c-fibres, while beta1 mRNA was virtually absent in these cell types but was expressed in 100% of large-diameter neurons. In the spinal cord, beta3 transcript was present specifically in layers I/II (substantia gelatinosa) and layer X, while beta1 mRNA was expressed in all laminae throughout the grey matter. Since the pattern of beta3 expression in DRG appears to correlate with the TTX-resistant voltage-gated sodium channel subunit PN3, we co-expressed the two subunits in Xenopus oocytes. In this system, beta3 caused a 5-mV hyperpolarizing shift in the threshold of activation of PN3, and a threefold increase in the peak current amplitude when compared with PN3 expressed alone. On the basis of these results, we examined the expression of beta-subunits in the chronic constriction injury model of neuropathic pain. Results revealed a significant increase in beta3 mRNA expression in small-diameter sensory neurons of the ipsilateral DRG. These results show that beta3 is the dominant auxiliary sodium channel subunit in small-diameter neurons of the rat DRG and that it is significantly upregulated in a model of neuropathic pain.

Upregulation of the Voltage-Gated Sodium Channel β2 Subunit in Neuropathic Pain Models: Characterization of Expression in Injured and Non-Injured Primary Sensory Neurons

“…That this increase has functional significance was indicated by our observation that mechanical allodynia-like behavior after nerve injury was attenuated in ␤2 subunit null mutant mice. The ␤2 subunit remained elevated in DRG neurons for at least 4 weeks after peripheral nerve injury, and this appears to be independent of transcriptional regulation because no increase in ␤2 subunit mRNA transcript levels was detected, as with previous studies (Black et al, 1996;Shah et al, 2000;Takahashi et al, 2003). Nerve injury can induce expression of target genes by activating transcription factors such as ATF3, cAMP response element-binding protein, or c-jun, but protein synthesis in the nervous system can be also modulated without involving new transcription of mRNA by a modification of translational control.…”

Differential Expression of Sodium Channel β Subunits in Dorsal Root Ganglion Sensory Neurons

“…These studies indicate that all four isoforms of ␤ subunits (␤ 1 -␤ 4 ) are present in the DRG and that these subunits are differentially expressed in subpopulations of sensory neurons (12,15). ␤ 3 subunits are prominently expressed in small and medium neurons, whereas ␤ 1 and ␤ 4 are preferentially expressed in large neurons (4,16,17). ␤ 2 appears to be widely expressed in the DRG and does not show a clear preference for neuronal size (15,45).…”

“…Much of what is currently known about ␤ subunit expression in the DRG has been derived from immunocytochemistry and in situ hybridization (4,12,(15)(16)(17)(18)44). These studies indicate that all four isoforms of ␤ subunits (␤ 1 -␤ 4 ) are present in the DRG and that these subunits are differentially expressed in subpopulations of sensory neurons (12,15).…”

Electrophysiological Properties of Mutant Nav1.7 Sodium Channels in a Painful Inherited Neuropathy

“…Moreover, although Na v 1.7 currents exhibit similar properties in HEK293 cells and DRG neurons (Cummins et al, 1998;Herzog et al, 2003), it is also possible that the mutant and wild-type Na v 1.7 channels are differentially modulated in DRG neurons, and this might contribute to the disease phenotype. For example, our studies in HEK293 cells were done with coexpression of the ␤1 and ␤2 subunits, but DRG neurons also express other ␤ subunits such as ␤3 (Shah et al, 2000) that could impact the current properties. Na v 1.4 and Na v 1.7 currents exhibit distinct properties (Cummins et al, 1998) and could be differentially modulated by ␤ subunits, and this could also contribute to the different disease phenotypes.…”