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The sodium channel {beta}3-subunit induces multiphasic gating in Nav1.3 and affects fast inactivation via distinct intracellular regions.

Fiona S Cusdin, Daniel Nietlispach, Joseph Maman, Timothy J Dale, Andrew J Powell, Jeffrey J Clare, Antony P Jackson

, 2010 Jul 30 , ,

Electrical excitability in neurons depends on the activity of membrane-bound voltage gated sodium channels (Nav) that are assembled from an ion conducting alpha-subunit and often auxiliary beta-subunits. The alpha-subunit isoform Nav1.3 occurs in peripheral neurons together with the Nav beta3-subunit, both of which are co-ordinately up-regulated in rat DRG neurons following nerve injury. Here we examine the effect of the beta3-subunit on the gating behaviour of Nav1.3 using whole cell patch-clamp electrophysiology in HEK-293 cells. We show that beta3 depolarizes the voltage sensitivity of Nav1.3 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 beta3-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 Nav beta-subunit. We infer the presence of a region within the beta3-subunit intracellular domain that has a propensity to form a short amphipathic alpha-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 beta3 may contribute to the known hyperexcitability of peripheral neurons under those physiological conditions where expression of beta3 and Nav1.3 are both enhanced.