Functional modulation of the human voltage-gated sodium channel NaV1.8 by auxiliary β subunits

The voltage-gated sodium channel Na(v)1.8 mediates the tetrodotoxin-resistant (TTX-R) Na+ current in nociceptive primary sensory neurons, which has an important role in the transmission of painful stimuli. Here, we describe the functional modulation of the human Na(v)1.8 alpha-subunit in Xenopus oocytes by auxiliary beta subunits. We found that the beta 3 subunit down-regulated the maximal Na+ current amplitude and decelerated recovery from inactivation of hNa(v)1.8, whereas the beta 1 and beta 2 subunits had no such effects. The specific regulation of Na(v)1.8 by the beta 3 subunit constitutes a potential novel regulatory mechanism of the TTX-R Na+ current in primary sensory neurons with potential implications in chronic pain states. In particular, neuropathic pain states are characterized by a down-regulation of Na(v)1.8 accompanied by increased expression of the beta 3 subunit. Our results suggest that these two phenomena may be correlated, and that increased levels of the beta 3 subunit may directly contribute to the down-regulation of Na(v)1.8. To determine which domain of the beta 3 subunit is responsible for the specific regulation of hNa(v)1.8, we created chimeras of the beta 1 and beta 3 subunits and co-expressed them with the hNa(v)1.8 alpha-subunit in Xenopus oocytes. The intracellular domain of the beta 3 subunit was shown to be responsible for the down-regulation of maximal Na(v)1.8 current amplitudes. In contrast, the extracellular domain mediated the effect of the beta 3 subunit on hNa(v)1.8 recovery kinetics.