@article{MTMT: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},
	title = {Polyunsaturated fatty acid analogues differentially affect cardiac Na-V, Ca-V, and K-V channels through unique mechanisms},
	journal-iso = {ELIFE},
	journal = {ELIFE},
	volume = {9},
	unique-id = {31296300},
	issn = {2050-084X},
	abstract = {The cardiac ventricular action potential depends on several voltage-gated ion channels, including Na-V, Ca-V, and K-V channels. Mutations in these channels can cause Long QT Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden cardiac death. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics for LQTS because they are modulators of voltage-gated ion channels. Here we demonstrate that PUFA analogues vary in their selectivity for human voltage-gated ion channels involved in the ventricular action potential. The effects of specific PUFA analogues range from selective for a specific ion channel to broadly modulating cardiac ion channels from all three families (Na-V, Ca-V, and K-V). In addition, a PUFA analogue selective for the cardiac IKs channel (Kv7.1/KCNE1) is effective in shortening the cardiac action potential in human-induced pluripotent stem cell-derived cardiomyocytes. Our data suggest that PUFA analogues could potentially be developed as therapeutics for LQTS and cardiac arrhythmia.},
	keywords = {SUBUNIT; STRUCTURAL BASIS; KINETICS; ACTION-POTENTIALS; LONG-QT SYNDROME; VOLTAGE-DEPENDENT INACTIVATION; SODIUM-CHANNEL; Molecular physiology; SENSOR MOVEMENT},
	year = {2020},
	orcid-numbers = {Bohannon, Briana M./0000-0002-3720-1477}
}

@article{MTMT:31683986,
	author = {Jo, Sooyeon and Bean, Bruce P.},
	doi = {10.1124/mol.119.118380},
	title = {Lidocaine Binding Enhances Inhibition of Nav1.7 Channels by the Sulfonamide PF-05089771},
	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,
	author = {Rose, Pia and Schleimer, Jan-Hendrik and Schreiber, Susanne},
	doi = {10.1371/journal.pone.0236949},
	title = {Modifications of sodium channel voltage dependence induce arrhythmia-favouring dynamics of cardiac action potentials},
	journal-iso = {PLOS ONE},
	journal = {PLOS ONE},
	volume = {15},
	unique-id = {31745261},
	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,
	author = {Zhu, Wandi and Li, Tianbo and Silva, Jonathan R. and Chen, Jun},
	doi = {10.1038/s41598-020-67761-5},
	title = {Conservation and divergence in NaChBac and Na(V)1.7 pharmacology reveals novel drug interaction mechanisms},
	journal-iso = {SCI REP},
	journal = {SCIENTIFIC REPORTS},
	volume = {10},
	unique-id = {31503450},
	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,
	author = {Balleza, Daniel and Rosas, Mario E. and Romero-Romero, Sergio},
	doi = {10.1080/19336950.2019.1674242},
	title = {Voltage vs. Ligand I: Structural basis of the intrinsic flexibility of S3 segment and its significance in ion channel activation},
	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,
	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},
	title = {Molecular game theory for a toxin-dominant food chain model},
	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,
	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},
	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},
	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,
	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},
	title = {Predicting Patient Response to the Antiarrhythmic Mexiletine Based on Genetic Variation Personalized Medicine for Long QT Syndrome},
	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,
	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},
	title = {Distinct modulation of inactivation by a residue in the pore domain of voltage-gated Na+ channels: mechanistic insights from recent crystal structures},
	journal-iso = {SCI REP},
	journal = {SCIENTIFIC REPORTS},
	volume = {8},
	unique-id = {27351923},
	year = {2018},
	eissn = {2045-2322}
}

@article{MTMT:27352156,
	author = {Silva, Jonathan R},
	doi = {10.1016/j.bpj.2017.11.024},
	title = {How to Connect Cardiac Excitation to the Atomic Interactions of Ion Channels},
	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,
	author = {Gosselin-Badaroudine, P and Charnet, P and Collet, C and Chahine, M},
	doi = {10.1002/1873-3468.12897},
	title = {Metaflumizone inhibits the honeybee NaV1 channel by targeting recovery from slow inactivation},
	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,
	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},
	title = {Mechanisms and models of cardiac sodium channel inactivation},
	journal-iso = {CHANNELS},
	journal = {CHANNELS},
	volume = {11},
	unique-id = {27352158},
	issn = {1933-6950},
	year = {2017},
	eissn = {1933-6969},
	pages = {517-533}
}

@article{MTMT: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},
	title = {Depolarization of the conductance-voltage relationship in the Na(V)1.5 mutant, E1784K, is due to altered fast inactivation},
	journal-iso = {PLOS ONE},
	journal = {PLOS ONE},
	volume = {12},
	unique-id = {27145422},
	year = {2017},
	eissn = {1932-6203}
}

@article{MTMT:3320951,
	author = {Zhu, W and Voelker, TL and Varga, Zoltán and Schubert, AR and Nerbonne, JM and Silva, JR},
	doi = {10.1085/jgp.201711802},
	title = {Mechanisms of noncovalent β subunit regulation of NaV channel gating},
	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}
}