Regulation of Na+ channel inactivation by the DIII and DIV voltage-sensing domains

Hsu, Eric J.; Zhu, Wandi; Schubert, A.; Voelker, Taylor L.; Varga, Zoltán; Silva, Jonathan R.

doi:10.1085/jgp.201611678

Cited by 32 publications

(56 citation statements)

References 37 publications

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“…54 Later results also showed that the VSDs of DI-DIII are also likely involved with slower components of inactivation. 55,56 Work with inactivation deficient mutations shows that the DIII-VSD also participates in fast inactivation but only after pulses with durations of 100s of ms. 57,58 Together these results suggest a model where the hydrophobic IFM sequence of DIII-DIV linker quickly associates with DIV-VSD to initiate fast inactivation ( Fig. 4).…”

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confidence: 66%

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Mechanisms and models of cardiac sodium channel inactivation

et al. 2017

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Shortly after cardiac Na channels activate and initiate the action potential, inactivation ensues within milliseconds, attenuating the peak Na current, I and allowing the cell membrane to repolarize. A very limited number of Na channels that do not inactivate carry a persistent I, or late I. While late I is only a small fraction of peak magnitude, it significantly prolongs ventricular action potential duration, which predisposes patients to arrhythmia. Here, we review our current understanding of inactivation mechanisms, their regulation, and how they have been modeled computationally. Based on this body of work, we conclude that inactivation and its connection to late I would be best modeled with a "feet-on-the-door" approach where multiple channel components participate in determining inactivation and late I. This model reflects experimental findings showing that perturbation of many channel locations can destabilize inactivation and cause pathological late I.

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confidence: 66%

“…Inactivation is significantly determined by the DIII and DIV VSDs. 57 After channel activation, IFM associates with the DIV-VSD to control inactivation onset. After »100 ms, the IFM also associates with the DIII-VSD, supporting its activated conformation.…”

Section: Regulation Of Inactivation By Accessory Subunitsmentioning

confidence: 99%

Mechanisms and models of cardiac sodium channel inactivation

et al. 2017

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“…In Ca V 1.1, which is significantly more flexible for these segments, Calabrese et al have reported that only inactivation is mechanosensitive [104]. In both channels, fast inactivation is associated to a particlethe ballthat physically occludes the pore by interacting with other domains and which is part of an intracellular linker situated between domains DIII-DIV in Na V channels [49] or DI-DII in Ca V channels [101,102], both of them rigid. This evidence is consistent with the concept of segmental rigidity participating in large-scale molecular motions.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, CNG and domain IV of Ca V channels are highly flexible while K V 7, Hv1, TRPV, domain III of Ca V 2, domain I of Ca V 1 and domain III and IV of Na V channels are always rigid independently of the analyzed segment. Interestingly, in sodium channels, voltage-sensing domains III and IV, firmly established as participating in fast inactivation [48,49] show a rigid profile if they are compared with domains DI and DII, which are mainly associated to channel activation [50]. Finally, by comparing subfamilies K V 1 (Shaker), K V 2 (Shab), K V 3 (Shaw) and K V 4 (Shal) with members of the KCNH channel family (K V 10, K V 11 and K V 12) we found that the paddle motif as well as the length of S3-S4 linker, which is longer in K V 1-4 channels, are the main responsible conferring diverse flexibility profiles to the segment S3.…”

Section: Local Flexibilitymentioning

confidence: 99%

Voltage vs. Ligand I: Structural basis of the intrinsic flexibility of S3 segment and its significance in ion channel activation

2019

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We systematically predict the internal flexibility of the S3 segment, one of the most mobile elements in the voltage-sensor domain. By analyzing the primary amino acid sequences of V-sensor containing proteins, including Hv1, TPC channels and the voltage-sensing phosphatases, we established correlations between the local flexibility and modes of activation for different members of the VGIC superfamily. Taking advantage of the structural information available, we also assessed structural aspects to understand the role played by the flexibility of S3 during the gating of the pore. We found that S3 flexibility is mainly determined by two specific regions: (1) a short NxxD motif in the N-half portion of the helix (S3a), and (2) a short sequence at the beginning of the so-called paddle motif where the segment has a kink that, in some cases, divide S3 into two distinct helices (S3a and S3b). A good correlation between the flexibility of S3 and the reported sensitivity to temperature and mechanical stretch was found. Thus, if the channel exhibits high sensitivity to heat or membrane stretch, local S3 flexibility is low. On the other hand, high flexibility of S3 is preferentially associated to channels showing poor heat and mechanical sensitivities. In contrast, we did not find any apparent correlation between S3 flexibility and voltage or ligand dependence. Overall, our results provide valuable insights into the dynamics of channel-gating and its modulation.

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“…Extensive work has been done to characterize how each of the different voltage-sensing domains in Nav channels contribute to voltage-dependent activation and inactivation, many implicating DIV S4 in fast inactivation (6, 43). Recent work by Hsu and colleagues (2017) has also shown using voltage clamp fluorometry, the importance of both DIII and DIV in Nav channel inactivation (44). Our data suggest that PUFAs may interact with S4 segments involved in voltage-dependent inactivation, allowing PUFA analogues to left-shift the voltage dependence of inactivation.…”

Section: Discussionmentioning

confidence: 99%

Polyunsaturated fatty acid analogues differentially affect cardiac Na_v, Ca_v, and K_v channels through unique mechanisms

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Perez

et al. 2019

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20The cardiac ventricular action potential depends on several voltage-gated ion channels, 21 including Nav, Cav, and Kv channels. Mutations in these channels can cause Long QT 22 Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden cardiac 23 death. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics for 24 LQTS because they are modulators of voltage-gated ion channels. Here we 25 demonstrate that PUFA analogues vary in their selectivity for human voltage-gated ion 26 channels involved in the ventricular action potential. The effects of specific PUFA 27 analogues range from selective for a specific ion channel to broadly modulating all three 28 cardiac ion channels (NaV, CaL, and IKs). In addition, PUFA analogues do not modulate 29 these channels through a shared mechanism. Our data suggest that different PUFA 30 analogues could be tailored towards specific forms of LQTS, which are caused by 31 mutations in distinct cardiac ion channels, and thus restore a normal ventricular action 32 potential. 34Polyunsaturated fatty acids (PUFAs) are amphipathic molecules that have been 82 suggested to possess antiarrhythmic effects (29, 30). PUFAs are characterized by 83 having a long hydrocarbon tail with two or more double bonds, as well as having a 84 charged, hydrophilic head group (31). PUFAs, such as DHA and EPA, have been 85 shown to prevent cardiac arrhythmias in animal models and cultured cardiomyocytes by 86 inhibiting the activity of Nav and Cav channels (30,(32)(33)(34). Specifically, DHA and EPA 87 are thought to bind to discrete sites on the channel protein to stabilize the inactivated 88 states of the Nav and Cav channels (32, 35). Since the voltage sensors of Nav and Cav 89 channels are relatively homologous, it has been suggested that PUFAs act on the 90 voltage-sensing S4 segments that control inactivation in these channels (30, 32). Our 91 group has demonstrated that PUFAs and PUFA analogues also modulate the activity of 92 the Kv7.1/KCNE1 channel and work to promote voltage-dependent activation of the IKs 93 current (36-38). The mechanism through which PUFAs promote Kv7.1/KCNE1 94 activation is referred to as the lipoelectric hypothesis which involves the following: 1) the 95 PUFA molecule integrates into the membrane via its hydrocarbon tail and 2) the 96 negatively charged PUFA head group electrostatically attracts the positively charged S4 97 segment and facilitates the outward movement of S4, promoting IKs channel activation 98 (36). Our group has also demonstrated that PUFAs and modified PUFAs exert a second 99 effect on the pore of Kv7.1 through an additional electrostatic interaction with a lysine 100 residue (K326) in the S6 segment (39). This electrostatic interaction between the 101 negatively charged PUFA head group and K326 leads to an increase in maximal 102 conductance of the channel (Gmax) (39).103 104 6Some groups have suggested that PUFAs could modify Nav channels by causing a 105 leftward shift in voltage dependent inactivation through...

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Regulation of Na+ channel inactivation by the DIII and DIV voltage-sensing domains

Cited by 32 publications

References 37 publications

Mechanisms and models of cardiac sodium channel inactivation

Mechanisms and models of cardiac sodium channel inactivation

Voltage vs. Ligand I: Structural basis of the intrinsic flexibility of S3 segment and its significance in ion channel activation

Polyunsaturated fatty acid analogues differentially affect cardiac Na_v, Ca_v, and K_v channels through unique mechanisms

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Regulation of Na+ channel inactivation by the DIII and DIV voltage-sensing domains

Cited by 32 publications

References 37 publications

Mechanisms and models of cardiac sodium channel inactivation

Mechanisms and models of cardiac sodium channel inactivation

Voltage vs. Ligand I: Structural basis of the intrinsic flexibility of S3 segment and its significance in ion channel activation

Polyunsaturated fatty acid analogues differentially affect cardiac Nav, Cav, and Kv channels through unique mechanisms

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Polyunsaturated fatty acid analogues differentially affect cardiac Na_v, Ca_v, and K_v channels through unique mechanisms