@article{MTMT:33889929, title = {Differential regulation of cardiac sodium channels by intracellular fibroblast growth factors}, url = {https://m2.mtmt.hu/api/publication/33889929}, author = {Angsutararux, Paweorn and Dutta, Amal K. and Marras, Martina and Abella, Carlota and Mellor, Rebecca L. and Shi, Jingyi and Nerbonne, Jeanne M. and Silva, Jonathan R.}, doi = {10.1085/jgp.202213300}, journal-iso = {J GEN PHYSIOL}, journal = {JOURNAL OF GENERAL PHYSIOLOGY}, volume = {155}, unique-id = {33889929}, issn = {0022-1295}, abstract = {Voltage-gated sodium (Na-V) channels are responsible for the initiation and propagation of action potentials. In the heart, the predominant Na(V)1.5 alpha subunit is composed of four homologous repeats (I-IV) and forms a macromolecular complex with multiple accessory proteins, including intracellular fibroblast growth factors (iFGF). In spite of high homology, each of the iFGFs, iFGF11-iFGF14, as well as the individual iFGF splice variants, differentially regulates Na-V channel gating, and the mechanisms underlying these differential effects remain elusive. Much of the work exploring iFGF regulation of Na(V)1.5 has been performed in mouse and rat ventricular myocytes in which iFGF13VY is the predominant iFGF expressed, whereas investigation into Na(V)1.5 regulation by the human heart-dominant iFGF12B is lacking. In this study, we used a mouse model with cardiac-specific Fgf13 deletion to study the consequences of iFGF13VY and iFGF12B expression. We observed distinct effects on the voltage-dependences of activation and inactivation of the sodium currents (I-Na), as well as on the kinetics of peak I-Na decay. Results in native myocytes were recapitulated with human Na(V)1.5 heterologously expressed in Xenopus oocytes, and additional experiments using voltage-clamp fluorometry (VCF) revealed iFGF-specific effects on the activation of the Na(V)1.5 voltage sensor domain in repeat IV (VSD-IV). iFGF chimeras further unveiled roles for all three iFGF domains (i.e., the N-terminus, core, and C-terminus) on the regulation of VSD-IV, and a slower time domain of inactivation. We present here a novel mechanism of iFGF regulation that is specific to individual iFGF isoforms and that leads to distinct functional effects on Na-V channel/current kinetics.Intracellular fibroblast growth factors (iFGF) regulate voltage-gated sodium (Na-V) channel expression and gating. Using a mouse model and heterologous expression in Xenopus oocytes, we describe mechanisms of how iFGF alters Na-V channel activation and inactivation.}, year = {2023}, eissn = {1540-7748}, orcid-numbers = {Marras, Martina/0000-0001-6740-3806} } @article{MTMT:33246334, title = {Closed-state inactivation of cardiac, skeletal, and neuronal sodium channels is isoform specific}, url = {https://m2.mtmt.hu/api/publication/33246334}, author = {Brake, Niklas and Mancino, Adamo S. and Yan, Yuhao and Shimomura, Takushi and Kubo, Yoshihiro and Khadra, Anmar and Bowie, Derek}, doi = {10.1085/jgp.202112921}, journal-iso = {J GEN PHYSIOL}, journal = {JOURNAL OF GENERAL PHYSIOLOGY}, volume = {154}, unique-id = {33246334}, issn = {0022-1295}, abstract = {Combining electrophysiology and kinetic modeling, Brake et al. highlight the role of closed-state inactivation in the gating behavior of cardiac, skeletal muscle, and neuronal voltage-gated sodium channels.Voltage-gated sodium (Nav) channels produce the upstroke of action potentials in excitable tissues throughout the body. The gating of these channels is determined by the asynchronous movements of four voltage-sensing domains (VSDs). Past studies on the skeletal muscle Nav1.4 channel have indicated that VSD-I, -II, and -III are sufficient for pore opening, whereas VSD-IV movement is sufficient for channel inactivation. Here, we studied the cardiac sodium channel, Nav1.5, using charge-neutralizing mutations and voltage-clamp fluorometry. Our results reveal that both VSD-III and -IV are necessary for Nav1.5 inactivation, and that steady-state inactivation can be modulated by all VSDs. We also demonstrate that channel activation is partially determined by VSD-IV movement. Kinetic modeling suggests that these observations can be explained from the cardiac channel's propensity to enter closed-state inactivation (CSI), which is significantly higher than that of other Nav channels. We show that skeletal muscle Nav1.4, cardiac Nav1.5, and neuronal Nav1.6 all have different propensities for CSI and postulate that these differences produce isoform-dependent roles for the four VSDs.}, year = {2022}, eissn = {1540-7748}, orcid-numbers = {Brake, Niklas/0000-0002-4256-2832; Yan, Yuhao/0000-0003-0049-850X; Shimomura, Takushi/0000-0002-8109-535X; Kubo, Yoshihiro/0000-0001-6707-0837; Khadra, Anmar/0000-0002-8228-9914; Bowie, Derek/0000-0001-9491-8768} } @article{MTMT:33329596, title = {Intrinsic mechanisms in the gating of resurgent Na+ currents}, url = {https://m2.mtmt.hu/api/publication/33329596}, author = {Ransdell, Joseph L. and Moreno, Jonathan D. and Bhagavan, Druv and Silva, Jonathan R. and Nerbonne, Jeanne M.}, doi = {10.7554/eLife.70173 10.7554/eLife.70173.sa0 10.7554/eLife.70173.sa1 10.7554/eLife.70173.sa2}, journal-iso = {ELIFE}, journal = {ELIFE}, volume = {11}, unique-id = {33329596}, issn = {2050-084X}, abstract = {The resurgent component of the voltage-gated sodium current (I-NaR) is a depolarizing conductance, revealed on membrane hyperpolarizations following brief depolarizing voltage steps, which has been shown to contribute to regulating the firing properties of numerous neuronal cell types throughout the central and peripheral nervous systems. Although mediated by the same voltage-gated sodium (Nav) channels that underlie the transient and persistent Nav current components, the gating mechanisms that contribute to the generation of I-NaR remain unclear. Here, we characterized Nav currents in mouse cerebellar Purkinje neurons, and used tailored voltage-clamp protocols to define how the voltage and the duration of the initial membrane depolarization affect the amplitudes and kinetics of I-NaR. Using the acquired voltage-clamp data, we developed a novel Markov kinetic state model with parallel (fast and slow) inactivation pathways and, we show that this model reproduces the properties of the resurgent, as well as the transient and persistent, Nav currents recorded in (mouse) cerebellar Purkinje neurons. Based on the acquired experimental data and the simulations, we propose that resurgent Na+ influx occurs as a result of fast inactivating Nav channels transitioning into an open/conducting state on membrane hyperpolarization, and that the decay of I-NaR reflects the slow accumulation of recovered/opened Nav channels into a second, alternative and more slowly populated, inactivated state. Additional simulations reveal that extrinsic factors that affect the kinetics of fast or slow Nav channel inactivation and/or impact the relative distribution of Nav channels in the fast- and slow-inactivated states, such as the accessory Nav beta 4 channel subunit, can modulate the amplitude of I-NaR.}, keywords = {MOUSE; Markov modeling; Nav channel gating; sodium channel gating; INaR; cerebellar Purkinje neurons}, year = {2022}, eissn = {2050-084X}, orcid-numbers = {Bhagavan, Druv/0000-0002-1396-0532} } @article{MTMT:33911510, title = {Molecular Modeling of Cardiac Sodium Channel with Mexiletine}, url = {https://m2.mtmt.hu/api/publication/33911510}, author = {Zhorov, Boris S. S.}, doi = {10.3390/membranes12121252}, journal-iso = {MEMBRANES-BASEL}, journal = {MEMBRANES (BASEL)}, volume = {12}, unique-id = {33911510}, abstract = {A sodium channel blocker mexiletine (MEX) is used to treat chronic pain, myotonia and some arrhythmias. Mutations in the pore domain (PD) of voltage-gated sodium channels differently affect tonic block (TB) and use-dependent block (UDB) by MEX. Previous studies identified several MEX-sensing residues in the hNav1.5 channel and demonstrated that the channel block by MEX increases with activation of the voltage-sensing domain III (VSDIII), whereas MEX stabilizes the activated state of VSDIII. Structural rationales for these observations are unclear. Here, Monte Carlo (MC) energy minimizations were used to dock MEX and its more potent analog, Thio-Me2, into the hNav1.5 cryo-EM structure with activated VSDs and presumably inactivated PD. Computations yielded two ensembles of ligand binding poses in close contacts with known MEX-sensing residues in helices S6(III), S6(IV) and P1(IV). In both ensembles, the ligand NH3 group approached the cation-attractive site between backbone carbonyls at the outer-pore bottom, while the aromatic ring protruded ether into the inner pore (putative UDB pose) or into the III/IV fenestration (putative TB pose). In silico deactivation of VSDIII shifted helices S4-S5(III), S5(III), S6(III) and S6(IV) and tightened the TB site. In a model with activated VSDIII and three resting VSDs, MC-minimized energy profile of MEX pulled from the TB site towards lipids shows a deep local minimum due to interactions with 11 residues in S5(III), P1(III), S6(III) and S6(IV). The minimum may correspond to an interim binding site for MEX in the hydrophobic path to the TB site along the lipid-exposed sides of repeats III and IV where 15 polar and aromatic residues would attract cationic blockers. The study explains numerous experimental data and suggests the mechanism of allosteric modification of the MEX binding site by VSDIII.}, keywords = {molecular modeling; local anesthetics; tonic block; use-dependent block; Monte Carlo energy minimizations; voltage-sensing domains; hydrophobic access pathway}, year = {2022}, eissn = {2077-0375} } @article{MTMT:32999679, title = {Conformations of voltage-sensing domain III differentially define NaV channel closed- and open-state inactivation}, url = {https://m2.mtmt.hu/api/publication/32999679}, author = {Angsutararux, Paweorn and Kang, Po Wei and Zhu, Wandi and Silva, Jonathan R.}, doi = {10.1085/jgp.202112891}, journal-iso = {J GEN PHYSIOL}, journal = {JOURNAL OF GENERAL PHYSIOLOGY}, volume = {153}, unique-id = {32999679}, issn = {0022-1295}, abstract = {Voltage-gated Na+ (NaV) channels underlie the initiation and propagation of action potentials (APs). Rapid inactivation after NaV channel opening, known as open-state inactivation, plays a critical role in limiting the AP duration. However, NaV channel inactivation can also occur before opening, namely closed-state inactivation, to tune the cellular excitability. The voltagesensing domain (VSD) within repeat IV (VSD-IV) of the pseudotetrameric NaV channel alpha-subunit is known to be a critical regulator of NaV channel inactivation. Vet, the two processes of open- and closed-state inactivation predominate at different voltage ranges and feature distinct kinetics. How inactivation occurs over these different ranges to give rise to the complexity of NaV channel dynamics is unclear. Past functional studies and recent cryo-electron microscopy structures, however, reveal significant inactivation regulation from other NaV channel components. In this Hypothesis paper, we propose that the VSD of NaV repeat III (VSD-III), together with VSD-IV, orchestrates the inactivation-state occupancy of NaV channels by modulating the affinity of the intracellular binding site of the IFMT motif on the III-IV linker. We review and outline substantial evidence that VSD-III activates in two distinct steps, with the intermediate and fully activated conformation regulating closed- and open-state inactivation state occupancy by altering the formation and affinity of the IFMT crevice. A role of VSD-III in determining inactivation-state occupancy and recovery from inactivation suggests a regulatory mechanism for the state-dependent block by small-molecule anti-arrhythmic and anesthetic therapies.}, year = {2021}, eissn = {1540-7748}, orcid-numbers = {Angsutararux, Paweorn/0000-0003-1083-5004; Zhu, Wandi/0000-0003-0927-5687} } @article{MTMT:32164117, title = {Identification of structures for ion channel kinetic models}, url = {https://m2.mtmt.hu/api/publication/32164117}, author = {Mangold, Kathryn E. and Wang, Wei and Johnson, Eric K. and Bhagavan, Druv and Moreno, Jonathan D. and Nerbonne, Jeanne M. and Silva, Jonathan R.}, doi = {10.1371/journal.pcbi.1008932}, journal-iso = {PLOS COMPUT BIOL}, journal = {PLOS COMPUTATIONAL BIOLOGY}, volume = {17}, unique-id = {32164117}, issn = {1553-734X}, abstract = {Author summary Markov models of ion channel dynamics have evolved as experimental advances have improved our understanding of channel function. Past studies have examined limited sets of various structures for Markov models of channel dynamics. Here, we present a computational routine designed to thoroughly search for Markov model topologies for simulating whole-cell currents. We tested this method on two distinct types of voltage-gated cardiac ion channels and found the number of states and connectivity required to recapitulate experimentally observed kinetics. Successful models identified with this approach have certain characteristics in common, suggesting that model structures are determined by the experimental data. Incorporation of these models into higher scale action potential and cable (an approximation of one-dimensional action potential propagation) simulations, identified key channel phenomena that were required for proper function. These methods provide a route to create functional channel models that can be used for action potential simulation without pre-defining their structure ahead of time. Markov models of ion channel dynamics have evolved as experimental advances have improved our understanding of channel function. Past studies have examined limited sets of various topologies for Markov models of channel dynamics. We present a systematic method for identification of all possible Markov model topologies using experimental data for two types of native voltage-gated ion channel currents: mouse atrial sodium currents and human left ventricular fast transient outward potassium currents. Successful models identified with this approach have certain characteristics in common, suggesting that aspects of the model topology are determined by the experimental data. Incorporating these channel models into cell and tissue simulations to assess model performance within protocols that were not used for training provided validation and further narrowing of the number of acceptable models. The success of this approach suggests a channel model creation pipeline may be feasible where the structure of the model is not specified a priori.}, keywords = {MECHANISMS; ALGORITHM; RECOVERY; CURRENTS; Excitability; Biochemical Research Methods; AGGREGATED MARKOV-MODELS}, year = {2021}, eissn = {1553-7358}, orcid-numbers = {Bhagavan, Druv/0000-0002-1396-0532; Silva, Jonathan R./0000-0002-3696-3955} } @article{MTMT:33529875, title = {A Novel Spider Toxin Inhibits Fast Inactivation of the Na(v)1.9 Channel by Binding to Domain III and Domain IV Voltage Sensors}, url = {https://m2.mtmt.hu/api/publication/33529875}, author = {Peng, Shuijiao and Chen, Minzhi and Xiao, Zhen and Xiao, Xin and Luo, Sen and Liang, Songping and Zhou, Xi and Liu, Zhonghua}, doi = {10.3389/fphar.2021.778534}, journal-iso = {FRONT PHARMACOL}, journal = {FRONTIERS IN PHARMACOLOGY}, volume = {12}, unique-id = {33529875}, abstract = {Venomous animals have evolved to produce peptide toxins that modulate the activity of voltage-gated sodium (Na-v) channels. These specific modulators are powerful probes for investigating the structural and functional features of Na-v channels. Here, we report the isolation and characterization of delta-theraphotoxin-Gr4b (Gr4b), a novel peptide toxin from the venom of the spider Grammostola rosea. Gr4b contains 37-amino acid residues with six cysteines forming three disulfide bonds. Patch-clamp analysis confirmed that Gr4b markedly slows the fast inactivation of Na(v)1.9 and inhibits the currents of Na(v)1.4 and Na(v)1.7, but does not affect Na(v)1.8. It was also found that Gr4b significantly shifts the steady-state activation and inactivation curves of Na(v)1.9 to the depolarization direction and increases the window current, which is consistent with the change in the ramp current. Furthermore, analysis of Na(v)1.9/Na(v)1.8 chimeric channels revealed that Gr4b preferentially binds to the voltage-sensor of domain III (DIII VSD) and has additional interactions with the DIV VSD. The site-directed mutagenesis analysis indicated that N1139 and L1143 in DIII S3-S4 linker participate in toxin binding. In sum, this study reports a novel spider peptide toxin that may slow the fast inactivation of Na(v)1.9 by binding to the new neurotoxin receptor site-DIII VSD. Taken together, these findings provide insight into the functional role of the Na-v channel DIII VSD in fast inactivation and activation.}, keywords = {Na(V)1; 9; Fast inactivation; domain III voltage-sensor; spider peptide toxin; neurotoxin receptor site}, year = {2021}, eissn = {1663-9812} } @article{MTMT:32440367, title = {Modulation of the effects of class Ib antiarrhythmics on cardiac Na(V)1.5-encoded channels by accessory Na-V beta subunits}, url = {https://m2.mtmt.hu/api/publication/32440367}, author = {Zhu, Wandi and Wang, Wei and Angsutararux, Paweorn and Mellor, Rebecca L. and Isom, Lori L. and Nerbonne, Jeanne M. and Silva, Jonathan R.}, doi = {10.1172/jci.insight.143092}, journal-iso = {JCI INSIGHT}, journal = {JCI INSIGHT}, volume = {6}, unique-id = {32440367}, abstract = {Native myocardial voltage-gated sodium (Na-V) channels function in macromolecular complexes comprising a pore-forming (alpha) subunit and multiple accessory proteins. Here, we investigated the impact of accessory Na-V beta 1 and Na-V beta 3 subunits on the functional effects of 2 well-known class Ib antiarrhythmics, lidocaine and ranolazine, on the predominant Na-V channel alpha subunit, Na(V)1.5, expressed in the mammalian heart. We showed that both drugs stabilized the activated conformation of the voltage sensor of domain-III (DIII-VSD) in Na(V)1.5. In the presence of Na-V beta 1, the effect of lidocaine on the DIII-VSD was enhanced, whereas the effect of ranolazine was abolished. Mutating the main class Ib drug-binding site, F1760, affected but did not abolish the modulation of drug block by Na-V beta 1/beta 3. Recordings from adult mouse ventricular myocytes demonstrated that loss of Scn1b (Na-V beta 1) differentially affected the potencies of lidocaine and ranolazine. In vivo experiments revealed distinct ECG responses to i.p. injection of ranolazine or lidocaine in WT and Scn1b-null animals, suggesting that Na-V beta 1 modulated drug responses at the whole-heart level. In the human heart, we found that SCN1B transcript expression was 3 times higher in the atria than ventricles, differences that could, in combination with inherited or acquired cardiovascular disease, dramatically affect patient response to class Ib antiarrhythmic therapies.}, year = {2021}, eissn = {2379-3708}, orcid-numbers = {Zhu, Wandi/0000-0003-0927-5687} } @article{MTMT:31296300, title = {Polyunsaturated fatty acid analogues differentially affect cardiac Na-V, Ca-V, and K-V channels through unique mechanisms}, url = {https://m2.mtmt.hu/api/publication/31296300}, author = {Bohannon, Briana M. and de, la Cruz Alicia and Wu, Xiaoan and Jowais, Jessica J. and Perez, Marta E. and Liin, Sara I and Larsson, H. Peter}, doi = {10.7554/eLife.51453}, journal-iso = {ELIFE}, journal = {ELIFE}, volume = {9}, unique-id = {31296300}, issn = {2050-084X}, keywords = {SUBUNIT; STRUCTURAL BASIS; KINETICS; ACTION-POTENTIALS; LONG-QT SYNDROME; VOLTAGE-DEPENDENT INACTIVATION; SODIUM-CHANNEL; Molecular physiology; SENSOR MOVEMENT}, year = {2020}, eissn = {2050-084X}, orcid-numbers = {Bohannon, Briana M./0000-0002-3720-1477} } @article{MTMT:31683986, title = {Lidocaine Binding Enhances Inhibition of Nav1.7 Channels by the Sulfonamide PF-05089771}, url = {https://m2.mtmt.hu/api/publication/31683986}, author = {Jo, Sooyeon and Bean, Bruce P.}, doi = {10.1124/mol.119.118380}, journal-iso = {MOL PHARMACOL}, journal = {MOLECULAR PHARMACOLOGY}, volume = {97}, unique-id = {31683986}, issn = {0026-895X}, abstract = {PF-05089771 is an aryl sulfonamide Nav1.7 channel blocker that binds to the inactivated state of Nav1.7 channels with high affinity but binds only weakly to channels in the resting state. Such aryl sulfonamide Nav1.7 channel blockers bind to the extracellular surface of the S1-S4 voltage-sensor segment of homologous Domain 4, whose movement is associated with inactivation. This binding site is different from that of classic sodium channel inhibitors like lidocaine, which also bind with higher affinity to the inactivated state than the resting state but bind at a site within the pore of the channel. The common dependence on gating state with distinct binding sites raises the possibility that inhibition by aryl sulfonamides and by classic local anesthetics might show an interaction mediated by their mutual state dependence. We tested this possibility by examining the state-dependent inhibition by PF-05089771 and lidocaine of human Nav1.7 channels expressed in human embryonic kidney 293 cells. At -80 mV, where a small fraction of channels are in an inactivated state under drug-free conditions, inhibition by PF-05089771 was both enhanced and speeded in the presence of lidocaine. The results suggest that lidocaine binding to the channel enhances PF-05089771 inhibition by altering the equilibrium between resting states (with D4S4 in the inner position) and inactivated states (with D4S4 in the outer position). The gating state-mediated interaction between the compounds illustrates a principle applicable to many state-dependent agents.SIGNIFICANCE STATEMENTThe results show that lidocaine enhances the degree and rate of inhibition of Nav1.7 channels by the aryl sulfonamide compound PF-05089771, consistent with state-dependent binding by lidocaine increasing the fraction of channels presenting a high-affinity binding site for PF-05089771 and suggesting that combinations of agents targeted to the pore-region binding site of lidocaine and the external binding site of aryl sulfonamides may have synergistic actions.}, year = {2020}, eissn = {1521-0111}, pages = {377-383} } @article{MTMT:31745261, title = {Modifications of sodium channel voltage dependence induce arrhythmia-favouring dynamics of cardiac action potentials}, url = {https://m2.mtmt.hu/api/publication/31745261}, author = {Rose, Pia and Schleimer, Jan-Hendrik and Schreiber, Susanne}, doi = {10.1371/journal.pone.0236949}, journal-iso = {PLOS ONE}, journal = {PLOS ONE}, volume = {15}, unique-id = {31745261}, issn = {1932-6203}, abstract = {Heart arrhythmia is a pathological condition where the sequence of electrical impulses in the heart deviates from the normal rhythm. It is often associated with specific channelopathies in cardiac tissue, yet how precisely the changes in ionic channels affect the electrical activity of cardiac cells is still an open question. Even though sodium channel mutations that underlie cardiac syndromes like the Long-Q-T and the Brugada-syndrome are known to affect a number of channel parameters simultaneously, previous studies have predominantly focused on the persistent late component of the sodium current as the causal explanation for an increased risk of heart arrhythmias in these cardiac syndromes. A systematic analysis of the impact of other important sodium channel parameters is currently lacking. Here, we investigate the reduced ten-Tusscher-model for single human epicardium ventricle cells and use mathematical bifurcation analysis to predict the dependence of the cardiac action potential on sodium channel activation and inactivation time-constants and voltage dependence. We show that, specifically, shifts of the voltage dependence of activation and inactivation curve can lead to drastic changes in the action potential dynamics, inducing oscillations of the membrane potential as well as bistability. Our results not only demonstrate a new way to induce multiple co-existing states of excitability (biexcitability) but also emphasize the critical role of the voltage dependence of sodium channel activation and inactivation curves for the induction of heart-arrhythmias.}, year = {2020}, eissn = {1932-6203} } @article{MTMT:31503450, title = {Conservation and divergence in NaChBac and Na(V)1.7 pharmacology reveals novel drug interaction mechanisms}, url = {https://m2.mtmt.hu/api/publication/31503450}, author = {Zhu, Wandi and Li, Tianbo and Silva, Jonathan R. and Chen, Jun}, doi = {10.1038/s41598-020-67761-5}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {10}, unique-id = {31503450}, issn = {2045-2322}, abstract = {Voltage-gated Na+ (Na-V) channels regulate homeostasis in bacteria and control membrane electrical excitability in mammals. Compared to their mammalian counterparts, bacterial Na-V channels possess a simpler, fourfold symmetric structure and have facilitated studies of the structural basis of channel gating. However, the pharmacology of bacterial Na-V remains largely unexplored. Here we systematically screened 39 Na-V modulators on a bacterial channel (NaChBac) and characterized a selection of compounds on NaChBac and a mammalian channel (human Na(V)1.7). We found that while many compounds interact with both channels, they exhibit distinct functional effects. For example, the local anesthetics ambroxol and lidocaine block both Na(V)1.7 and NaChBac but affect activation and inactivation of the two channels to different extents. The voltage-sensing domain targeting toxin BDS-I increases Na(V)1.7 but decreases NaChBac peak currents. The pore binding toxins aconitine and veratridine block peak currents of Na(V)1.7 and shift activation (aconitine) and inactivation (veratridine) respectively. In NaChBac, they block the peak current by binding to the pore residue F224. Nonetheless, aconitine has no effect on activation or inactivation, while veratridine only modulates activation of NaChBac. The conservation and divergence in the pharmacology of bacterial and mammalian Na-V channels provide insights into the molecular basis of channel gating and will facilitate organism-specific drug discovery.}, year = {2020}, eissn = {2045-2322} } @article{MTMT:31066622, title = {Voltage vs. Ligand I: Structural basis of the intrinsic flexibility of S3 segment and its significance in ion channel activation}, url = {https://m2.mtmt.hu/api/publication/31066622}, author = {Balleza, Daniel and Rosas, Mario E. and Romero-Romero, Sergio}, doi = {10.1080/19336950.2019.1674242}, journal-iso = {CHANNELS}, journal = {CHANNELS}, volume = {13}, unique-id = {31066622}, issn = {1933-6950}, abstract = {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.}, keywords = {channel activation; VOLTAGE SENSOR; Local flexibility; S3 segment}, year = {2019}, eissn = {1933-6969}, pages = {455-476}, orcid-numbers = {Balleza, Daniel/0000-0002-6848-9135} } @article{MTMT:31567853, title = {Molecular game theory for a toxin-dominant food chain model}, url = {https://m2.mtmt.hu/api/publication/31567853}, author = {Li, Bowen and Silva, Jonathan R. and Lu, Xiancui and Luo, Lei and Wang, Yunfei and Xu, Lizhen and Aierken, Aerziguli and Shynykul, Zhanserik and Kamau, Peter Muiruri and Luo, Anna and Yang, Jian and Su, Deyuan and Yang, Fan and Cui, Jianmin and Yang, Shilong and Lai, Ren}, doi = {10.1093/nsr/nwz097}, journal-iso = {NATL SCI REV}, journal = {NATIONAL SCIENCE REVIEW}, volume = {6}, unique-id = {31567853}, issn = {2095-5138}, abstract = {Animal toxins that are used to subdue prey and deter predators act as the key drivers in natural food chains and ecosystems. However, the predators of venomous animals may exploit feeding adaptation strategies to overcome toxins their prey produce. Much remains unknown about the genetic and molecular game process in the toxin-dominant food chain model. Here, we show an evolutionary strategy in different trophic levels of scorpion-eating amphibians, scorpions and insects, representing each predation relationship in habitats dominated by the paralytic toxins of scorpions. For scorpions preying on insects, we found that the scorpion alpha-toxins irreversibly activate the skeletal muscle sodium channel of their prey (insect, BgNa(V)1) through a membrane delivery mechanism and an efficient binding with the Asp/Lys-Tyr motif of BgNa(V)1. However, in the predatory game between frogs and scorpions, with a single point mutation (Lys to Glu) in this motif of the frog's skeletal muscle sodium channel (fNa(V)1.4), fNa(V)1.4 breaks this interaction and diminishes muscular toxicity to the frog; thus, frogs can regularly prey on scorpions without showing paralysis. Interestingly, this molecular strategy also has been employed by some other scorpion-eating amphibians, especially anurans. In contrast to these amphibians, the Asp/Lys-Tyr motifs are structurally and functionally conserved in other animals that do not prey on scorpions. Together, our findings elucidate the protein-protein interacting mechanism of a toxin-dominant predator-prey system, implying the evolutionary game theory at a molecular level.}, keywords = {RECEPTOR; TOXIN; amphibian; Scorpion; molecular game}, year = {2019}, eissn = {2053-714X}, pages = {1191-1200}, orcid-numbers = {Yang, Fan/0000-0002-0520-5254} } @article{MTMT:31066621, title = {Gating control of the cardiac sodium channel Nav1.5 by its?3-subunit involves distinct roles for a transmembrane glutamic acid and the extracellular domain}, url = {https://m2.mtmt.hu/api/publication/31066621}, author = {Salvage, Samantha C. and Zhu, Wandi and Habib, Zaki F. and Hwang, Soyon S. and Irons, Jennifer R. and Huang, Christopher L. H. and Silva, Jonathan R. and Jackson, Antony P.}, doi = {10.1074/jbc.RA119.010283}, journal-iso = {J BIOL CHEM}, journal = {JOURNAL OF BIOLOGICAL CHEMISTRY}, volume = {294}, unique-id = {31066621}, issn = {0021-9258}, abstract = {The auxiliary ?3-subunit is an important functional regulator of the cardiac sodium channel Nav1.5, and some ?3 mutations predispose individuals to cardiac arrhythmias. The ?3-subunit uses its transmembrane ?-helix and extracellular domain to bind to Nav1.5. Here, we investigated the role of an unusually located and highly conserved glutamic acid (Glu-176) within the ?3 transmembrane region and its potential for functionally synergizing with the ?3 extracellular domain (ECD). We substituted Glu-176 with lysine (E176K) in the WT ?3-subunit and in a ?3-subunit lacking the ECD. Patch-clamp experiments indicated that the E176K substitution does not affect the previously observed ?3-dependent depolarizing shift of V-? of steady-state inactivation but does attenuate the accelerated recovery from inactivation conferred by the WT ?3-subunit. Removal of the ?3-ECD abrogated both the depolarizing shift of steady-state inactivation and the accelerated recovery, irrespective of the presence or absence of the Glu-176 residue. We found that steady-state inactivation and recovery from inactivation involve movements of the S4 helices within the DIII and DIV voltage sensors in response to membrane potential changes. Voltage-clamp fluorometry revealed that the E176K substitution alters DIII voltage sensor dynamics without affecting DIV. In contrast, removal of the ECD significantly altered the dynamics of both DIII and DIV. These results imply distinct roles for the ?3-Glu-176 residue and the ?3-ECD in regulating the conformational changes of the voltage sensors that determine channel inactivation and recovery from inactivation.}, keywords = {FLUORESCENCE; Electrophysiology; CARDIOMYOPATHY; sodium channel; cardiovascular disease; protein structure; voltage clamp fluorescence}, year = {2019}, eissn = {1083-351X}, pages = {19752-19763} } @article{MTMT:30566716, title = {Predicting Patient Response to the Antiarrhythmic Mexiletine Based on Genetic Variation Personalized Medicine for Long QT Syndrome}, url = {https://m2.mtmt.hu/api/publication/30566716}, author = {Zhu, Wandi and Mazzanti, Andrea and Voelker, Taylor L. and Hou, Panpan and Moreno, Jonathan D. and Angsutararux, Paweorn and Naegle, Kristen M. and Priori, Silvia G. and Silva, Jonathan R.}, doi = {10.1161/CIRCRESAHA.118.314050}, journal-iso = {CIRC RES}, journal = {CIRCULATION RESEARCH}, volume = {124}, unique-id = {30566716}, issn = {0009-7330}, abstract = {Rationale: Mutations in the SCN5A gene, encoding the alpha subunit of the Nav1.5 channel, cause a life-threatening form of cardiac arrhythmia, long QT syndrome type 3 (LQT3). Mexiletine, which is structurally related to the Na+ channel-blocking anesthetic lidocaine, is used to treat LQT3 patients. However, the patient response is variable, depending on the genetic mutation in SCN5A.}, keywords = {ION CHANNELS; Electrophysiology; LONG QT SYNDROME; mexiletine; Precision Medicine}, year = {2019}, eissn = {1524-4571}, pages = {539-552}, orcid-numbers = {Mazzanti, Andrea/0000-0002-0208-2172} } @article{MTMT:27351923, title = {Distinct modulation of inactivation by a residue in the pore domain of voltage-gated Na+ channels: mechanistic insights from recent crystal structures}, url = {https://m2.mtmt.hu/api/publication/27351923}, author = {Cervenka, Rene and Lukács, Péter and Gawali, Vaibhavkumar S and Ke, Song and Koenig, Xaver and Rubi, Lena and Zarrabi, Touran and Hilber, Karlheinz and Sandtner, Walter and Stary-Weinzinger, Anna and Todt, Hannes}, doi = {10.1038/s41598-017-18919-1}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {8}, unique-id = {27351923}, issn = {2045-2322}, year = {2018}, eissn = {2045-2322} } @article{MTMT:27352156, title = {How to Connect Cardiac Excitation to the Atomic Interactions of Ion Channels}, url = {https://m2.mtmt.hu/api/publication/27352156}, author = {Silva, Jonathan R}, doi = {10.1016/j.bpj.2017.11.024}, journal-iso = {BIOPHYS J}, journal = {BIOPHYSICAL JOURNAL}, volume = {114}, unique-id = {27352156}, issn = {0006-3495}, year = {2018}, eissn = {1542-0086}, pages = {259-266} } @article{MTMT:27121330, title = {Metaflumizone inhibits the honeybee NaV1 channel by targeting recovery from slow inactivation}, url = {https://m2.mtmt.hu/api/publication/27121330}, author = {Gosselin-Badaroudine, P and Charnet, P and Collet, C and Chahine, M}, doi = {10.1002/1873-3468.12897}, journal-iso = {FEBS LETT}, journal = {FEBS LETTERS}, volume = {591}, unique-id = {27121330}, issn = {0014-5793}, year = {2017}, eissn = {1873-3468}, pages = {3842-3849} } @article{MTMT:27352158, title = {Mechanisms and models of cardiac sodium channel inactivation}, url = {https://m2.mtmt.hu/api/publication/27352158}, author = {Mangold, Kathryn E and Brumback, Brittany D and Angsutararux, Paweorn and Voelker, Taylor L and Zhu, Wandi and Kang, Po Wei and Moreno, Jonathan D and Silva, Jonathan R}, doi = {10.1080/19336950.2017.1369637}, journal-iso = {CHANNELS}, journal = {CHANNELS}, volume = {11}, unique-id = {27352158}, issn = {1933-6950}, year = {2017}, eissn = {1933-6969}, pages = {517-533} } @article{MTMT:27145422, title = {Depolarization of the conductance-voltage relationship in the Na(V)1.5 mutant, E1784K, is due to altered fast inactivation}, url = {https://m2.mtmt.hu/api/publication/27145422}, author = {Peters, Colin H and Yu, Alec and Zhu, Wandi and Silva, Jonathan R and Ruben, Peter C}, doi = {10.1371/journal.pone.0184605}, journal-iso = {PLOS ONE}, journal = {PLOS ONE}, volume = {12}, unique-id = {27145422}, issn = {1932-6203}, year = {2017}, eissn = {1932-6203} } @article{MTMT:3320951, title = {Mechanisms of noncovalent β subunit regulation of NaV channel gating}, url = {https://m2.mtmt.hu/api/publication/3320951}, author = {Zhu, W and Voelker, TL and Varga, Zoltán and Schubert, AR and Nerbonne, JM and Silva, JR}, doi = {10.1085/jgp.201711802}, journal-iso = {J GEN PHYSIOL}, journal = {JOURNAL OF GENERAL PHYSIOLOGY}, volume = {149}, unique-id = {3320951}, issn = {0022-1295}, year = {2017}, eissn = {1540-7748}, pages = {813-831} }