The sodium channel {beta}3-subunit induces multiphasic gating in NaV1.3 and affects fast inactivation via distinct intracellular regions.

ABSTRACT: Electrical excitability in neurons depends on the activity of membrane-bound voltage gated sodium channels (Na(v)) that are assembled from an ion conducting ?-subunit and often auxiliary ?-subunits. The ?-subunit isoform Na(v)1.3 occurs in peripheral neurons together with the Na(v) ?3-subunit, both of which are coordinately up-regulated in rat dorsal root ganglion neurons after nerve injury. Here we examine the effect of the ?3-subunit on the gating behavior of Na(v)1.3 using whole cell patch clamp electrophysiology in HEK-293 cells. We show that ?3 depolarizes the voltage sensitivity of Na(v)1.3 activation and inactivation and induces biphasic components of the inactivation curve. We detect both a fast and a novel slower component of inactivation, and we show that the ?3-subunit increases the fraction of channels inactivating by the slower component. Using CD and NMR spectroscopy, we report the first structural analysis of the intracellular domain of any Na(v) ?-subunit. We infer the presence of a region within the ?3-subunit intracellular domain that has a propensity to form a short amphipathic ?-helix followed by a structurally disordered sequence, and we demonstrate a role for both of these regions in the selective stabilization of fast inactivation. The complex gating behavior induced by ?3 may contribute to the known hyperexcitability of peripheral neurons under those physiological conditions where expression of ?3 and Na(v)1.3 are both enhanced.

SUBMITTER: Cusdin FS 

PROVIDER: S-EPMC2963402 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature