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Michael E Green Alisher M Kariev


Voltage gated K+ channels have been the subject of intensive study for over a half century. They are found in all cells; together with Nachannels, they are responsible for the nerve impulse, and play a key role in other excitable tissue, particularly the heart. Malfunctions due to mutation lead to a range of diseases, referred to as channelopathies. The mechanism by which the channels open and close, called gating, has been studied extensively; there is a range of standard models. All have in common a transmembrane segment of the channel protein moving in response to depolarization of the membrane, thereby pulling open a section of the channel at the intracellular end of the membrane; this allows Kions into the channel pore, producing a current of ions out from the cell. The motion of the ions is preceded by a capacitative current, the gating current, which is attributed to positive charges on the putatively mobile transmembrane segment. The evidence supporting this class of models is examined and reinterpreted to show that the evidence does not require the motion of a segment of protein. This and other evidence is instead considered in terms of a model in which protons provide the gating current; when these are at the intracellular terminus of the protein, they close the channel, while the channel is open when they are at the extracellular end. This model is supported by quantum calculations that are larger than have been previously reported for a protein system. Some of the calculations include most of the voltage sensing domain, and others the pore of the channel, with the hydration and cosolvation of the ion specified.

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GREEN, Michael E; KARIEV, Alisher M. WATER AND H+ TRANSFER IN VOLTAGE GATED K+ CHANNEL FUNCTION, WITH EVIDENCE FROM QUANTUM CALCULATIONS.. Medical Research Archives, [S.l.], v. 4, n. 7, nov. 2016. ISSN 2375-1924. Available at: <https://journals.ke-i.org/index.php/mra/article/view/725>. Date accessed: 21 july 2018.
Ion channels, gating, solvation, voltage sensing domain, quantum calculations
Review Articles


Abbott, G. W. (2006). "Molecular mechanisms of cardiac voltage-gated potassium channelopathies." Curr. Pharm. Des. 12(28): 3631-3644.

Akhtar, S., O. Shamotienko, M. Papakosta, F. Ali and J. O. Dolly (2002). "Characteristics of brain Kv1 channels tailored to mimic native counterparts by tandem linkage of α subunits: implications for K+ channelopathies." J. Biol. Chem. 277(19): 16376-16382.

Alicata, D. A., M. A. Rayner and J. A. Starkus (1990). "Sodium Channel activation mechanisms: Insights from deuterium oxide substitution." Biophysical Journal 57: 745-758.

Armstrong, C. M. and F. Bezanilla (1974). "Charge movement associated with the opening and closing of of the activation gates of the Na channels." J. Gen. Physiol. 63: 533-552.

Asamoah, O. K., J. P. Wuskell, L. M. Loew and F. Bezanilla (2003). "A Fluorometric Approach to Local Electric Field Measurements in a Voltage-Gated Ion Channel." Neuron 37: 85-97.

Batulan, Z., G. A. Haddad and R. Blunck (2010). "An Intersubunit Interaction between S4-S5 Linker and S6 Is Responsible for the Slow Off-gating Component in Shaker K+ Channels." J. Biol. Chem. 285(18): 14005-14019.

Blunck, R. and Z. Batulan (2012). "Mechanism of electromechanical coupling in voltage-gated potassium channels." Front. Pharmacol. Ion Channels Channelopathies 3(Sept.): 166.

Chen, X., Q. Wang, F. Ni and J. Ma (2010). "Structure of the full-length Shaker potassium channel Kv1.2 by normal-mode-based X-ray crystallographic refinement." Proc Natl Acad Sci U S A 107(25): 11352-11357.

Chen, X., Q. Wang, F. Ni and J. Ma (2010). "Structure of the full-length Shaker potassium channel Kv1.2 by normal-mode-based X-ray crystallographic refinement." Proc. Natl Acad Sci. 107: 11352-11357.

CM, A. and F. Bezanilla (1977). "Inactivation of the sodium channel. II. Gating current experiments." J. Gen'l Physiol. 70: 567-590.

DeCaen, P. G., V. Yarov-Yarovoy, Y. Zhao, T. Scheuer and W. A. Catterall (2008). "Disulfide locking a sodium channel voltage sensor reveals ion pair formation during activation." Proc. Natl. Acad. Sci. U. S. A. 105(39): 15142-15147.

Delemotte, L., M. L. Klein and M. Tarek (2012). "Molecular dynamics simulations of voltage-gated cation channels: insights on voltage-sensor domain function and modulation." Front. Pharmacol. Ion Channels Channelopathies 3(May): 97.

Doyle, D. A., J. M. Cabral, R. A. Pfuetzner, A. Kuo, J. M. Gulbis, S. L. Cohen, B. T. Chait and R. MacKinnon (1998). "The structure of the potassium channel: molecular basis of K+ conduction and selectivity." Science 280: 69-77.

E, N., Sakmann B and S. JH (1978). "The extracellular patch clamp: a method for resolving currents through individual open channels in biological membranes." Pflueger's Archiv 375: 219-228.

Fatade, A., J. Snowhite and M. E. Green (2000). "A Resonance Model gives the Response to Membrane Potential for an Ion Channel: II. Simplification of the Calculation, and Prediction of Stochastic Resonance." J. Theor. Biol. 206(3): 387-393.

Faure, E., G. Starek, H. McGuire, S. Berneche and R. Blunck (2012). "A Limited 4 Å Radial Displacement of the S4-S5 Linker Is Sufficient for Internal Gate Closing in Kv Channels." J. Biol. Chem. 287(47): 40091-40098.

Freites, J. A., D. J. Tobias, H. G. von and S. H. White (2005). "Interface connections of a transmembrane voltage sensor." Proc. Natl. Acad. Sci. U. S. A. 102(Copyright (C) 2012 American Chemical Society (ACS). All Rights Reserved.): 15059-15064.

Frisch, M. J. T., G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. (2016). "Gaussian09, Rev. E01."

Glendening, E. D., A. E. Reed, J. E. Carpenter and W. F. "NBO Version 3.1."

Gonzalez-Perez, V., K. Stack, K. Boric and D. Naranjo (2010). "Reduced voltage sensitivity in a K+-channel voltage sensor by electric field remodeling." Proc. Natl Acad Sci. 107: 5178-5183.

Green, M. E. (1989). "Electrorheological effects and gating of membrane channels." J.Theor. Biol. 138: 413-428.

Green, M. E. (2005). "A possible role for phosphate in complexing the arginines of S4 in voltage gated channels." J. Theor. Biol. 233: 337-341.

Green, M. E. (2008). "Consequences of Phosphate-Arginine Complexes in Voltage Gated Ion Channels." Channels 2: 395-400.

Hille, B. (2001). Ion Channels of Excitable Membranes. Sunderland, MA, Sinauer Associates.

Hodgkin, A. L. and A. F. Huxley (1952). "The components of membrane conductance in the giant axon of Loligo." J. Physiol. (Lond) 116: 473-496.

Hodgkin, A. L. and A. F. Huxley (1952). "Currents carried by sodium and potassium ions through the giant membrane of Loligo." J. Physiol. (Lond) 116: 449-472.

Hodgkin, A. L. and A. F. Huxley (1952). "The dual effect of membrane potential on sodium conductance in the giant axon of Loligo." J. Physiol. (Lond) 116: 497-506.

Ishida, I. G., G. E. Rangel-Yescas, J. Carrasco-Zanini and L. D. Islas (2015). "Voltage-dependent gating and gating charge measurements in the Kv1.2 potassium channel." J. Gen. Physiol. 145(4): 345-358.

Jensen, M. O., V. Jogini, D. W. Borhani, A. E. Leffler, R. O. Dror and D. E. Shaw (2012). "Mechanism of voltage gating in potassium channels." Science (Washington, DC, U. S.) 336(Copyright (C) 2012 American Chemical Society (ACS). All Rights Reserved.): 229-233.

Kariev, A. M. and M. E. Green (2009). "Quantum calculations on water in the KcsA channel cavity with permeant and non-permeant ions." Biochim. Biophys. Acta (Biomembranes) 1788: 1188-1192.

Kariev, A. M. and M. E. Green (2012). "Voltage Gated Ion Channel Function: Gating, Conduction, and the Role of Water and Protons." Int'l J. Molec. Sci. 13: 1680-1709.

Kariev, A. M. and M. E. Green (2015). "Caution is required in interpretation of mutations in the voltage sensing domain of voltage gated channels as evidence for gating mechanisms." Int. J. Mol. Sci. 16(1): 1627-1643.

Kariev, A. M. and M. E. Green (2015). "Quantum Effects in a Simple Ring with Hydrogen Bonds " J. Phys. Chem. B 119: 5962-5969.

Karlin, A. and M. H. Akabas (1998). "Substituted-cysteine accessibility method." Methods in Enzymology 293: 123-145.

Keynes, R. D. and E. Rojas (1974). "Kinetics and steady-state properties of the charged system controlling sodium conductance in the squid giant axon." J. Physiol. (Lond.) 239: 393-434.

Kim, J.-B. (2014). " Channelopathies." Korean J. Pediatr 57: 1-18.

Kintzer, A. F. and R. M. Stroud (2016). "Structure, inhibition and regulation of two-pore channel TPC1 from Arabidopsis thaliana." Nature (London, U. K.) 531(7593): 258-264.

Kosolapov, A., L. Tu, J. Wang and C. Deutsch (2004). "Structure acquisition of the T1 domain of Kv1.3 during biogenesis." Neuron 44(2): 295-307.

LeMasurier, M., L. Heginbotham and C. Miller (2001). "KcsA: It's a potassium channel." J. Gen'l Physiol. 118: 303-313.

Liao, S. and M. E. Green (2011). "Quantum calculations on salt bridges with water: Potentials, structure, and properties." Comput. Theo. Chem 963: 207-214.

Long, S. B., E. B. Campbell and R. MacKinnon (2005). "Crystal structure of a mammalian voltage-dependent Shaker family K+ channel " Science 309: 897-903.

Minor, D. L., Jr., Y.-F. Lin, B. C. Mobley, A. Avelar, Y. N. Jan, L. Y. Jan and J. M. Berger (2000). "The polar T1 interface is linked to conformational changes that open the voltage-gated potassium channel." Cell (Cambridge, Mass.) 102(5): 657-670.

Moroni, A. and G. Thiel (2006). "Flip-flopping salt bridges gate an ion-channel." Nat. Chem. Biol 2: 572-573.

Nguyen, T. P. and R. Horn (2002). "Movement and crevices around a sodium channel S3 segment." J. Gen'l. Physiol. 120: 419-436.

Noda, M., T. Shimizu, T. Tanabe, T. Takai, T. Kayano, T. Ikeda, H. Takahashi, H. Nakayama, N. Kanaoka, N. Minamino, K. Kangawa, H. Matsuo, M. A. Raftery, T. Hirose, S. Inayama, H. Hayashida, T. Miyata and S. Numa (1984). "Primary structure of electrophorus electricus sodium channel deduced from cDNA sequence." Nature 312: 121-127.

Papazian, D. M., X. M. Shao, S.-A. Seoh, A. F. Mock, Y. Huang and D. H. Wainstock (1995). "Electrostatic interactions of S4 voltage sensor in Shaker K+ channel." Neuron 14: 1293-1301.

Pinental, D., J. M. Donlea, C. B. Talbot, S. M. Song, A. J. F. Thurston and G. Miiesenbock (2016). "Operation of a Homeostatic Sleep Switch." Nature.

Robbins, C. A. and B. L. Tempel (2012). "Kv1.1 and Kv1.2: similar channels, different seizure models." Epilepsia 53 Suppl 1: 134-141.

Sapronova, A., V. S. Bystrov and M. E. Green (2003). "Water, proton transfer, and hydrogen bonding in ion channel gating." Front Biosci 8: s1356-1370.

Sapronova, A. V., V. S. Bystrov and M. E. Green (2003). "Ion channel gating and proton transport." J. Mol. Struct. (THEOCHEM) 630: 297-307.

Schauf, C. L. and J. O. Bullock (1980). "Solvent substitution as a probe of channel gating in Myxicola: differential effects of D2O on some components of membrane conductance." Biophys,. J. 30: 295-306.

Schauf, C. L. and J. O. Bullock (1982). "Solvent substitution as a probe of channel gating in Myxicola." Biophys,. J. 37: 441-452.

Schmidt, D., Q.-X. Jiang and R. MacKinnon (2006). "Phospholipids and the origin of cationic gating charges in voltage sensors." Nature (London, U. K.) 444(7120): 775-779.

Serratrice, G., J.-P. Azulay, J. Serratrice and S. Attarian (2004). "From Morvan's disease to potassium channelopathies." Bull. Acad. Natl. Med. (Paris, Fr.) 188(2): 233-245.

Sigg, D., F. Bezanilla and E. Stefani (2003). "Fast gating in the Shaker K+ channel and the energy landscape of activation." Proc. Natl Acad. Sci USA 100: 7611-7615.

Starace, D. M. and F. Bezanilla (2001). "Histidine scanning mutagenesis of uncharged residues of the Shaker K+ channel S4 segment." Biophys. J. 80: 217a.

Starace, D. M., E. Stefani and F. Bezanilla (1997). "Voltage-dependent proton transport by the voltage sensor of the Shaker K+ channel." Neuron 19: 1319-1327.

Stefani, E., D. Sigg and F. Bezanilla (2000). "Correlation between the early component of gating current and total gating current in Shaker K channels." Biophysical Journal 78: 7A.

Thompson, A. N., D. J. Posson, P. V. Parsa and C. M. Nimigean (2008). "Molecular mechanism of pH sensing in KcsA potassium channels." Proc. Nat'l Academy of Sciences 105: 6900-6905.

Tigerholm, J. and E. Fransen (2011). "Reversing Nerve Cell Pathology by Optimizing Modulatory Action on Target Ion Channels." Biophys. J. 101(8): 1871-1879.

Tronin, A., C. Nordgren, J. Strzalka, I. Kuzmenko, V. Lauter, J. Freites, D. Tobias and J. Blasie (2016). Investigating the mechanism of electromechanical coupling in voltage-gated ion channels by time-resolved x-ray & neutron interferometry, American Chemical Society.

Weinhold, F. (2012). "Natural Bond Orbital Analysis: A Critical Overview of Relationships to Alternative Bonding Perspectives." J. Comput. Chem. 33: 2363-2379.

Whicher, J. R. and R. MacKinnon (2016). "Structure of the voltage-gated K+ channel Eag1 reveaks an akternative voltage-sensing mechanism." Science 353: 664-669.

WN, Z., H. T. and A. RW (1990). "Restoration of inactivation in mutants of Shaker potassium channels by a peptide derived from ShB." Science 250: 568-571.

Yin, J. and M. E. Green (1998). "Intermolecular proton transfer between two methylamine molecules with an external electric field in the gas phase." J. Phys. Chem. A 102: 7181-7190.

Zhao, L.-L., Z. Qi, X.-E. Zhang, L.-J. Bi and G. Jin (2010). "Regulatory role of the extreme C-terminal end of the S6 inner helix in C-terminal-truncated Kv1.2 channel activation " Cell Biol. International 34: 433-439.

Zhao, W. and Y. Chen (2016). "Progress in Research of KV1.1 and KV1.3 Channels as Therapeutic Targets." Curr. Top. Med. Chem. (Sharjah, United Arab Emirates) 16(16): 1877-1885.

Zheng, J. and M. Trudeau, Eds. (2015). Handbook of Ion Channels. Boca Raton, Florida, CRC Press.

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