Sodium channel β2 subunits regulate tetrodotoxin-sensitive sodium channels in small dorsal root ganglion neurons and modulate the response to pain

Voltage-gated sodium channel (Na(v)1) beta 2 subunits modulate channel gating, assembly, and cell-surface expression in CNS neurons in vitro and in vivo. beta 2 expression increases in sensory neurons after nerve injury, and development of mechanical allodynia in the spared nerve injury model is attenuated in beta 2-null mice. Thus, we hypothesized that beta 2 modulates electrical excitability in dorsal root ganglion (DRG) neurons in vivo. We compared sodium currents (I-Na) in small DRG neurons from beta 2(-/-) and beta 2(-/-) mice to determine the effects of beta 2 on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Nav1 in vivo. Small-fast DRG neurons acutely isolated from beta 2(-/-) mice showed significant decreases in TTX-S I-Na compared with beta 2(+/+) neurons. This decrease included a 51% reduction in maximal sodium conductance with no detectable changes in the voltage dependence of activation or inactivation. TTX-S, but not TTX-R, I-Na activation and inactivation kinetics in these cells were slower in beta 2(-/-) mice compared with controls. The selective regulation of TTX-S I-Na was supported by reductions in transcript and protein levels of TTX-S Na(v)1s, particularly Na(v)1.7. Low-threshold mechanical sensitivity was preserved in beta 2(-/-) mice, but they were more sensitive to noxious thermal stimuli than wild type whereas their response during the late phase of the formalin test was attenuated. Our results suggest that beta 2 modulates TTX-S Na(v)1 mRNA and protein expression resulting in increased TTX-S I-Na and increases the rates of TTX-S Na(v)1 activation and inactivation in small-fast DRG neurons in vivo. TTX-R I-Na were not significantly modulated by beta 2.