Left-Shifted Nav Channels in Injured Bilayer: Primary Targets for Neuroprotective Nav Antagonists?

Abstract

Mechanical, ischemic, and inflammatory injuries to voltage-gated sodium channel (Nav)-rich membranes of axon initial segments and nodes of Ranvier render Nav channels dangerously leaky. By what means? The behavior of recombinant Nav1.6 (Wang et al., 2009) leads us to postulate that, in neuropathologic conditions, structural degradation of axolemmal bilayer fosters chronically left-shifted Nav channel operation, resulting in ENa rundown. This “sick excitable cell Nav-leak” would encompass left-shifted fast- and slow-mode based persistent INa (i.e., Iwindow and slow-inactivating INa). Bilayer-damage-induced electrophysiological dysfunctions of native-Nav channels, and effects on inhibitors on those channels, should, we suggest, be studied in myelinated axons, exploiting INa(V,t) hysteresis data from sawtooth ramp clamp. We hypothesize that (like dihydropyridines for Ca channels), protective lipophilic Nav antagonists would partition more avidly into disorderly bilayers than into the well-packed bilayers characteristic of undamaged, healthy plasma membrane. Whereas inhibitors using aqueous routes would access all Navs equally, differential partitioning into “sick bilayer” would co-localize lipophilic antagonists with “sick-Nav channels,” allowing for more specific targeting of impaired cells. Molecular fine-tuning of Nav antagonists to favor more avid partitioning into damaged than into intact bilayers could reduce side effects. In potentially salvageable neurons of traumatic and/or ischemic penumbras, in inflammatory neuropathies, in muscular dystrophy, in myocytes of cardiac infarct borders, Nav-leak driven excitotoxicity overwhelms cellular repair mechanisms. Precision-tuning of a lipophilic Nav antagonist for greatest efficacy in mildly damaged membranes could render it suitable for the prolonged continuous administration needed to allow for the remodeling of the excitable membranes, and thus functional recovery.

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

“…One possibility is that Na ϩ currents are especially sensitive to cell sickness/injury. In studies in both skeletal muscle and axons, it appears that damage triggers a hyperpolarized shift in the voltage dependence of the Na ϩ current activation and inactivation as well as a reduction in maximal current density (72,195,494). In injured cells with a depolarized resting potential, a hyperpolarized shift in the voltage dependence of inactivation would result in increased channel inactivation to reduce excitability.…”

Force Spectroscopy Measurements Show That Cortical Neurons Exposed to Excitotoxic Agonists Stiffen before Showing Evidence of Bleb Damage

“…In damaged excitable cell membranes, both NMDA channels and voltage-gated channels (including Cav and Nav and K) are considered “leaky”; they activate too easily [15,35–39]. In sick excitable cells, progressive bleb-damage would therefore contribute to lethal excitotoxic cascades [40,41]. In experimental stroke, even with NMDA channels blocked, the Nav-rich axon initial segments of cortical neurons suffer profound excitotoxic membrane damage (as evidenced by Ca ++ -protease fragments of spectrin) [20]: presumably, ATP depletion fosters a vicious cycle of rising [Na + ] int and [Ca ++ ] int , thence bleb-damage and further Nav-leak and ATP depletion [40].…”

Spontaneous Excitation Patterns Computed for Axons with Injury-like Impairments of Sodium Channels and Na/K Pumps

“…Hippocampal neurons exposed to the industrial compound, melamine, also show Nav-CLS and exhibit hyperexcitability [16]. In neurons and muscle fibers, left-shift of Nav availability (i.e., steady-state inactivation) [17] is reported for many damaging and/or toxic conditions (see Table 1 of [3]) and for membrane fluidizing conditions [18]; fast activation also becomes left-shifted in muscles (e.g. [19]) and neurons (e.g.…”