Binding of sodium channel inhibitors to hyperpolarized and depolarized conformations of the channel

Lenkey, Nora; Karoly, Robert; Epresi, N.; Vizi, E.S.; Mike, Arpad

doi:10.1016/j.neuropharm.2010.08.005

Cited by 30 publications

(71 citation statements)

References 56 publications

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“…A Nav channel has four voltage sensor domains and complex gating kinetics; this simplified scheme emphasizes voltage-dependent ( V ) activation [closed, open (C,O)], plus inactivation (I) to an open-like but occluded state in each of the two major modes (Active and Relaxed). The smaller letters (CA… and CR…) serve as a reminder that a full kinetic scheme (e.g., Taddese and Bean, 2002; Lenkey et al, 2011) would have many more states. Structural changes underlying mode switching, a feature of all voltage-gated proteins, are not yet understood (Villalba-Galea et al, 2008).…”

Section: Nav Channel Gating Mode Terminologymentioning

confidence: 99%

“…Structural changes underlying mode switching, a feature of all voltage-gated proteins, are not yet understood (Villalba-Galea et al, 2008). During prolonged depolarizations and hyperpolarizations, inter-mode transitions (vertical arrows), which are voltage-independent (Villalba-Galea et al, 2008), would drive the Nav system toward I R and C A (“ inactivated ” and “ resting ” in the parlance of Lenkey et al, 2011), respectively. Macroscopic I Na ( t ) includes I Na-fast (fast, transient, or broadly speaking, Hodgkin–Huxley type) plus I Na-slow (also variously called “persistent,” “slowly inactivating,” “non-inactivating”), which flow through open Active and Relaxed mode Nav channels (O A , O R ), respectively.…”

Section: Nav Channel Gating Mode Terminologymentioning

confidence: 99%

“…Importantly, the “subthreshold persistent current” of pacemaker neurons (Taddese and Bean, 2002) and of first-nodes (Kole, 2011) is a g Na-fast ( V ) based phenomenon, as is CLS. So-called “persistent current inhibitors” (e.g., riluzole, ranolazine) principally act by stabilizing non-conducting Relaxed mode states (large asterisk), but they also cause use-dependent ↓ I Na-fast , perhaps through binding to Active mode channels (Lenkey et al, 2011; though inhibitor-bound C R states (small asterisk) might contribute to ↓ [C A ] and thence to ↓ [O A ]).…”

Section: Nav Channel Gating Mode Terminologymentioning

confidence: 99%

“…These lipophilic compounds preferentially bind and stabilize Nav channels in non-conducting slow-gating states (Song et al, 1997; Antzelevitch et al, 2011). Often called “persistent current” blockers, these drug molecules are especially effective at stabilizing slow mode Nav in non-conducting states and at higher concentrations they inhibit fast-mode channels (Jo and Bean, 2011; Lenkey et al, 2011). Because of severe side effects (Waxman, 2008), however, none of the available Nav antagonists is routinely used to counter the devastating, slow-developing consequences of traumatic brain injury described at the neurological level as diffuse axonal injury (Wolf et al, 2001; Iwata et al, 2004) though for spinal injury, riluzole trial are underway (Cadotte and Fehlings, 2011).…”

Section: Nav Inhibitorsmentioning

confidence: 99%

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

Morris¹,

Boucher²,

Joós³

2012

Front. Pharmacol.

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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.

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Section: Nav Channel Gating Mode Terminologymentioning

confidence: 99%

Section: Nav Channel Gating Mode Terminologymentioning

confidence: 99%

Section: Nav Channel Gating Mode Terminologymentioning

confidence: 99%

Section: Nav Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

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

Morris¹,

Boucher²,

Joós³

2012

Front. Pharmacol.

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“…It is noteworthy that metaflumizone did not significantly affect the level of resting inhibition by lidocaine that was evident upon depolarization after zero prepulses. Resting and inactivated sodium channels may possess fundamentally distinct drug binding sites (Hille, 1977;Lenkey et al, 2011). Thus, the ability of metaflumizone to antagonize lidocaine inhibition of fast-inactivated but not resting sodium channels offers further evidence for different drug receptor conformations on resting and inactivated sodium channels.…”

Section: Metaflumizone Action At Local Anesthetic Receptor 371mentioning

confidence: 99%

Role of the Local Anesthetic Receptor in the State-Dependent Inhibition of Voltage-Gated Sodium Channels by the Insecticide Metaflumizone

Stein

Soderlund

2011

Mol Pharmacol

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Sodium channel inhibitor (SCI) insecticides selectively target voltage-gated sodium (Na v ) channels in the slow-inactivated state by binding at or near the local anesthetic receptor within the sodium channel pore. Metaflumizone is a new insecticide for the treatment of fleas on domesticated pets and has recently been reported to block insect sodium channels in the slow-inactivated state, thereby implying that it is also a member of the SCI class. Using the two-electrode voltage-clamp technique, we examined metaflumizone inhibition of rat Na v 1.4 sodium channels expressed in Xenopus laevis oocytes. Metaflumizone selectively inhibited Na v 1.4 channels at potentials that promoted slow inactivation and shifted the voltage dependence of slow inactivation in the direction of hyperpolarization. Metaflumizone perfusion at a hyperpolarized holding potential also shifted the conductance-voltage curve for activation in the direction of depolarization and antagonized use-dependent lidocaine inhibition of fast-inactivated sodium channels, actions not previously observed with other SCI insecticides. We expressed mutated Na v 1.4/F1579A and Na v 1.4/Y1586A channels to investigate whether metaflumizone shares the domain IV segment S6 (DIV-S6) binding determinants identified for other SCI insecticides. Consistent with previous investigations of SCI insecticides on rat Na v 1.4 channels, the F1579A mutation reduced sensitivity to block by metaflumizone, whereas the Y1586A mutation paradoxically increased the sensitivity to metaflumizone. We conclude that metaflumizone selectively inhibits slow-inactivated Na v 1.4 channels and shares DIV-S6 binding determinants with other SCI insecticides and therapeutic drugs. However, our results suggest that metaflumizone interacts with resting and fast-inactivated channels in a manner that is distinct from other compounds in this insecticide class.

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Coupled left-shift of Nav channels: modeling the Na+-loading and dysfunctional excitability of damaged axons

BoucherPierre-Alexandre

2012

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Injury to neural tissue renders voltage-gated Na⁺ (Nav) channels leaky. Even mild axonal trauma initiates Na⁺-loading, leading to secondary Ca²⁺-loading and white matter degeneration. The nodal isoform is Nav1.6 and for Nav1.6-expressing HEK-cells, traumatic whole cell stretch causes an immediate tetrodotoxin-sensitive Na⁺-leak. In stretch-damaged oocyte patches, Nav1.6 current undergoes damage-intensity dependent hyperpolarizing- (left-) shifts, but whether left-shift underlies injured-axon Nav-leak is uncertain. Nav1.6 inactivation (availability) is kinetically limited by (coupled to) Nav activation, yielding coupled left-shift (CLS) of the two processes: CLS should move the steady-state Nav1.6 "window conductance" closer to typical firing thresholds. Here we simulated excitability and ion homeostasis in free-running nodes of Ranvier to assess if hallmark injured-axon behaviors--Na⁺-loading, ectopic excitation, propagation block--would occur with Nav-CLS. Intact/traumatized axolemma ratios were varied, and for some simulations Na/K pumps were included, with varied in/outside volumes. We simulated saltatory propagation with one mid-axon node variously traumatized. While dissipating the [Na⁺] gradient and hyperactivating the Na/K pump, Nav-CLS generated neuropathic pain-like ectopic bursts. Depending on CLS magnitude, fraction of Nav channels affected, and pump intensity, tonic or burst firing or nodal inexcitability occurred, with [Na⁺] and [K⁺] fluctuating. Severe CLS-induced inexcitability did not preclude Na⁺-loading; in fact, the steady-state Na⁺-leaks elicited large pump currents. At a mid-axon node, mild CLS perturbed normal anterograde propagation, and severe CLS blocked saltatory propagation. These results suggest that in damaged excitable cells, Nav-CLS could initiate cellular deterioration with attendant hyper- or hypo-excitability. Healthy-cell versions of Nav-CLS, however, could contribute to physiological rhythmic firing.

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Binding of sodium channel inhibitors to hyperpolarized and depolarized conformations of the channel

Cited by 30 publications

References 56 publications

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

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

Role of the Local Anesthetic Receptor in the State-Dependent Inhibition of Voltage-Gated Sodium Channels by the Insecticide Metaflumizone

Coupled left-shift of Nav channels: modeling the Na+-loading and dysfunctional excitability of damaged axons

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