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

ABSTRACT

The voltage-gated sodium channel Nav1.8 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 Nav1.8 α-subunit in Xenopus oocytes by auxiliary ß subunits. We found that the ß3 subunit down-regulated the maximal Na+ current amplitude and decelerated recovery from inactivation of hNav1.8, whereas the ß1 and ß2 subunits had no such effects. The specific regulation of Nav1.8 by the ß3 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 Nav1.8 accompanied by increased expression of the ß3 subunit. Our results suggest that these two phenomena may be correlated, and that increased levels of the ß3 subunit may directly contribute to the down-regulation of Nav1.8. To determine which domain of the ß3 subunit is responsible for the specific regulation of hNav1.8, we created chimeras of the ß1 and ß3 subunits and co-expressed them with the hNav1.8 α-subunit in Xenopus oocytes. The intracellular domain of the ß3 subunit was shown to be responsible for the down-regulation of maximal Nav1.8 current amplitudes. In contrast, the extracellular domain mediated the effect of the ß3 subunit on hNav1.8 recovery kinetics.