Functional modulation of the human voltage-gated sodium channel Na V 1.8 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 α-subunit in Xenopus oocytes by auxiliary β subunits. We found that the β3 subunit down-regulated the maximal Na ⁺ current amplitude and decelerated recovery from inactivation of hNa _v 1.8, whereas the β1 and β2 subunits had no such effects. The specific regulation of Na _v 1.8 by the β3 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 β3 subunit. Our results suggest that these two phenomena may be correlated, and that increased levels of the β3 subunit may directly contribute to the down-regulation of Na _v 1.8. To determine which domain of the β3 subunit is responsible for the specific regulation of hNa _v 1.8, we created chimeras of the β1 and β3 subunits and co-expressed them with the hNa _v 1.8 α-subunit in Xenopus oocytes. The intracellular domain of the β3 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 β3 subunit on hNa _v 1.8 recovery kinetics.