Altered Gating and Local Anesthetic Block Mediated by Residues in the  I-S6 and II-S6 Transmembrane Segments of Voltage-Dependent Na<sup>+</sup>  Channels

Kondratiev, Andrei; Tomaselli, Gordon F.

doi:10.1124/mol.64.3.741

Cited by 33 publications

(27 citation statements)

References 44 publications

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“…This suggests that the DIV S6 helical segment undergoes a conformational change upon repeated depolarization that exposes the previously buried/hidden face of Phe1760 to the permeation pathway and thus allows interaction with drugs that reside in the cavity formed by the S6 segments from all four domains. The idea of a conformational change, possibly a rotation, of DIV S6 during inactivation is supported by previous studies on voltage-gated sodium and potassium channels [55][56][57][58] . Future experiments will help elucidate the nature and extent of this use-dependent conformational change, as this information is crucial for not only understanding therapeutic inhibition, but also voltage-dependent sodium channel function.…”

Section: Discussionsupporting

confidence: 54%

Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

et al. 2011

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Cardiac sodium channels are established therapeutic targets for the management of inherited and acquired arrhythmias by class I anti-arrhythmic drugs (AADs). These drugs share a common target receptor bearing two highly conserved aromatic side chains, and are subdivided by the Vaughan-Williams classification system into classes Ia-c based on their distinct effects on the electrocardiogram. How can these drugs elicit distinct effects on the cardiac action potential by binding to a common receptor? Here we use fluorinated phenylalanine derivatives to test whether the electronegative surface potential of aromatic side chains contributes to inhibition by six class I AADs. Surprisingly, we find that class Ib AADs bind via a strong electrostatic cation-pi interaction, whereas class Ia and Ic AADs rely significantly less on this interaction. Our data shed new light on drug-target interactions underlying the inhibition of cardiac sodium channels by clinically relevant drugs and provide information for the directed design of AADs.

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Section: Discussionsupporting

confidence: 54%

Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

et al. 2011

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“…The time constant of this late phase (t 2 , Fig. 7) showed some variation between constructs but, in general, was on the order of 100-200 milliseconds, as reported previously (Vedantham and Cannon, 1999;Kondratiev and Tomaselli, 2003).…”

Section: Protocol Of Testing Time Course Of Recovery Frommentioning

confidence: 55%

Mechanism of Modification, by Lidocaine, of Fast and Slow Recovery from Inactivation of Voltage-Gated Na⁺ Channels

et al. 2015

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The clinically important suppression of high-frequency discharges of excitable cells by local anesthetics (LA) is largely determined by drug-induced prolongation of the time course of repriming (recovery from inactivation) of voltage-gated Na 1 channels. This prolongation may result from periodic drugbinding to a high-affinity binding site during the action potentials and subsequent slow dissociation from the site between action potentials ("dissociation hypothesis"). For many drugs it has been suggested that the fast inactivated state represents the high-affinity binding state. Alternatively, LAs may bind with high affinity to a native slow-inactivated state, thereby accelerating the development of this state during action potentials ("stabilization hypothesis"). In this case, slow recovery between action potentials occurs from enhanced native slow inactivation. To test these two hypotheses we produced serial cysteine mutations of domain IV segment 6 in rNa v 1.4 that resulted in constructs with varying propensities to enter fast-and slowinactivated states. We tested the effect of the LA lidocaine on the time course of recovery from short and long depolarizing prepulses, which, under drug-free conditions, recruited mainly fast-and slow-inactivated states, respectively. Among the tested constructs the mutation-induced changes in native slow recovery induced by long depolarizations were not correlated with the respective lidocaine-induced slow recovery after short depolarizations. On the other hand, for long depolarizations the mutation-induced alterations in native slow recovery were significantly correlated with the kinetics of lidocaine-induced slow recovery. These results favor the "dissociation hypothesis" for short depolarizations but the "stabilization hypothesis" for long depolarizations.

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“…Nevertheless, this does not necessarily exclude contribution by other domains. For example, amino acid residues of S4 (Sheets and Hanck, 2007) and S6 (Ragsdale et al, 1994;Li et al, 1999;Wang et al, 2000;Yarov-Yarovoy et al, 2001) in domains III and IV make significant contributions to use-dependent LA block, although effects of mutations in S6 of domains I and II on LA block were also observed (Nau et al, 1999;Wang et al, 2001;Yarov-Yarovoy et al, 2002;Kondratiev and Tomaselli, 2003). Moreover, a naturally occurred mutation S1710L in cardiac Na ϩ channels (equivalent to Ser1528 in domain IV) reduced use-dependent block by LA (Sasaki et al, 2004).…”

Section: Ss1 Mutations Alter Qx-314 Block 867mentioning

confidence: 99%

Novel Molecular Determinants in the Pore Region of Sodium Channels Regulate Local Anesthetic Binding

et al. 2009

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The pore of the Na ϩ channel is lined by asymmetric loops formed by the linkers between the fifth and sixth transmembrane segments (S5-S6). We investigated the role of the Nterminal portion (SS1) of the S5-S6 linkers in channel gating and local anesthetic (LA) block using site-directed cysteine mutagenesis of the rat skeletal muscle (Na V 1.4) channel. The mutants examined have variable effects on voltage dependence and kinetics of fast inactivation. Of the cysteine mutants immediately N-terminal to the putative DEKA selectivity filter in four domains, only Q399C in domain I and F1236C in domain III exhibit reduced use-dependent block. These two mutations also markedly accelerated the recovery from use-dependent block. Moreover, F1236C and Q399C significantly decreased the affinity of QX-314 for binding to its channel receptor by 8.5-and 3.3-fold, respectively. Oddly enough, F1236C enhanced stabilization of slow inactivation by both hastening entry into and delaying recovery from slow inactivation states. It is noteworthy that symmetric applications of QX-314 on both external and internal sides of F1236C mutant channels reduced recovery from use-dependent block, indicating an allosteric effect of external QX-314 binding on the recovery of availability of F1236C. These observations suggest that cysteine mutation in the SS1 region, particularly immediate adjacent to the DEKA ring, may lead to a structural rearrangement that alters binding of permanently charged QX-314 to its receptor. The results lend further support for a role for the selectivity filter region as a structural determinant for local anesthetic block.Sodium channels are transmembrane proteins that rapidly conduct electrical impulses throughout nerve and muscle. The channels have a modular structure, with distinct regions mediating gating and permeation. The pore-lining (P) segments, formed by the S5-S6 linkers, are the major determinants for selective ion flux, whereas the S4 transmembrane domain and the cytoplasmic III-IV interdomain linker figure prominently in activation and fast inactivation gating, respectively. The structural separation of function is not clearcut; mutations in the P segments are known to alter gating (Tomaselli et al

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Altered Gating and Local Anesthetic Block Mediated by Residues in the I-S6 and II-S6 Transmembrane Segments of Voltage-Dependent Na⁺ Channels

Cited by 33 publications

References 44 publications

Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

Mechanism of Modification, by Lidocaine, of Fast and Slow Recovery from Inactivation of Voltage-Gated Na⁺ Channels

Novel Molecular Determinants in the Pore Region of Sodium Channels Regulate Local Anesthetic Binding

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Altered Gating and Local Anesthetic Block Mediated by Residues in the I-S6 and II-S6 Transmembrane Segments of Voltage-Dependent Na+ Channels

Cited by 33 publications

References 44 publications

Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

Mechanism of Modification, by Lidocaine, of Fast and Slow Recovery from Inactivation of Voltage-Gated Na+ Channels

Novel Molecular Determinants in the Pore Region of Sodium Channels Regulate Local Anesthetic Binding

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Altered Gating and Local Anesthetic Block Mediated by Residues in the I-S6 and II-S6 Transmembrane Segments of Voltage-Dependent Na⁺ Channels

Mechanism of Modification, by Lidocaine, of Fast and Slow Recovery from Inactivation of Voltage-Gated Na⁺ Channels