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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Membrane trauma and Na⁺ leak from Nav1.6 channels

Neuroscience, Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa Canada

Submitted 7 October 2008 ; accepted in final form 31 July 2009

During brain trauma, white matter experiences shear and stretch forces that, without severing axons, nevertheless trigger their secondary degeneration. In central nervous system (CNS) trauma models, voltage-gated sodium channel (Nav) blockers are neuroprotective. This, plus the rapid tetrodotoxin-sensitive Ca²⁺ overload of stretch-traumatized axons, points to "leaky" Nav channels as a pivotal early lesion in brain trauma. Direct effects of mechanical trauma on neuronal Nav channels have not, however, been tested. Here, we monitor immediate responses of recombinant neuronal Nav channels to stretch, using patch-clamp and Na⁺-dye approaches. Trauma constituted either bleb-inducing aspiration of cell-attached oocyte patches or abrupt uniaxial stretch of cells on an extensible substrate. Nav1.6 channel transient current displayed irreversible hyperpolarizing shifts of steady-state inactivation [availability(V)] and of activation [g(V)] and, thus, of window current. Left shift increased progressively with trauma intensity. For moderately intense patch trauma, a 20-mV hyperpolarizing shift was registered. Nav1.6 voltage sensors evidently see lower energy barriers posttrauma, probably because of the different bilayer mechanics of blebbed versus intact membrane. Na⁺ dye-loaded human embryonic kidney (HEK) cells stably transfected with Nav1.6 were subjected to traumatic brain injury-like stretch. Cytoplasmic Na⁺ levels abruptly increased and the trauma-induced influx had a significant tetrodotoxin-sensitive component. Nav1.6 channel responses to cell and membrane trauma are therefore consistent with the hypothesis that mechanically induced Nav channel leak is a primary lesion in traumatic brain injury. Nav1.6 is the CNS node of Ranvier Nav isoform. When, during head trauma, nodes experienced bleb-inducing membrane damage of varying intensities, nodal Nav1.6 channels should immediately "leak" over a broadly left-smeared window current range.

sodium dye; stretch; shear; bleb