TY - JOUR
T1 - Spider toxin inhibits gating pore currents underlying periodic paralysis
AU - Männikkö, Roope
AU - Shenkarev, Zakhar O.
AU - Thor, Michael G.
AU - Berkut, Antonina A.
AU - Myshkin, Mikhail Yu
AU - Paramonov, Alexander S.
AU - Kulbatskii, Dmitrii S.
AU - Kuzmin, Dmitry A.
AU - Castañeda, Marisol Sampedro
AU - King, Louise
AU - Wilson, Emma R.
AU - Lyukmanova, Ekaterina N.
AU - Kirpichnikov, Mikhail P.
AU - Schorge, Stephanie
AU - Bosmans, Frank
AU - Hanna, Michael G.
AU - Kullmann, Dimitri M.
AU - Vassilevski, Alexander A.
N1 - Funding Information:
We thank Stephen C. Cannon (University of California, Los Angeles), Kenton J. Swartz (National Institute of Neurological Disorders and Stroke/NIH) and Baron Chanda (University of Wisconsin?Madison) for sharing the expression clones, as well as David E. Shaw (D. E. Shaw Research) for providing models of the KV1.2/2.1 channel in different states and Nikolay Petrosian for modelling VSD-I of NaV1.4. This work was funded, in part, by UK Medical Research Council Project Grant MR/M006948/1 (to R.M.), the Wellcome Trust (D.A.K. and D.M.K.), the Molecular and Cell Biology Program of the Russian Academy of Sciences (A.A.V. and Z.O.S.), and Russian Foundation for Basic Research Grant 16-34-01185 (to A.A.B.). NMR study was funded by Russian Science Foundation Grant 16-14-10338 (to Z.O.S.). NMR experiments were carried out using equipment provided by the core facility of the Shemyakin?Ovchinnikov Institute of Bioorganic Chemistry (supported by Russian Ministry of Education and Science Grant RFMEFI62117X0018). Parts of this work were supported by NIH Grant R01NS091352 (to F.B.). M.G.T. was funded by an MRC Centre for Neuromuscular Diseases PhD studentship. M.G.T., M.G.H., and R.M. are supported by the University College London Hospitals Biomedical Research Centre. We dedicate this paper to the memory of Professor Eugene Grishin under whose leadership the study of Heriaeus toxins has begun.
Funding Information:
We thank Stephen C. Cannon (University of California, Los Angeles), Kenton J. Swartz (National Institute of Neurological Disorders and Stroke/NIH) and Baron Chanda (University of Wisconsin–Madison) for sharing the expression clones, as well as David E. Shaw (D. E. Shaw Research) for providing models of the KV1.2/2.1 channel in different states and Nikolay Petrosian for modelling VSD-I of NaV1.4. This work was funded, in part, by UK Medical Research Council Project Grant MR/M006948/1 (to R.M.), the Wellcome Trust (D.A.K. and D.M.K.), the Molecular and Cell Biology Program of the Russian Academy of Sciences (A.A.V. and Z.O.S.), and Russian Foundation for Basic Research Grant 16-34-01185 (to A.A.B.). NMR study was funded by Russian Science Foundation Grant 16-14-10338 (to Z.O.S.). NMR experiments were carried out using equipment provided by the core facility of the Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry (supported by Russian Ministry of Education and Science Grant RFMEFI62117X0018). Parts of this work were supported by NIH Grant R01NS091352 (to F.B.). M.G.T. was funded by an MRC Centre for Neuromuscular Diseases PhD studentship. M.G.T., M.G.H., and R.M. are supported by the University College London Hospitals Biomedical Research Centre. We dedicate this paper to the memory of Professor Eugene Grishin under whose leadership the study of Heriaeus toxins has begun.
Funding Information:
ACKNOWLEDGMENTS. We thank Stephen C. Cannon (University of California, Los Angeles), Kenton J. Swartz (National Institute of Neurological Disorders and Stroke/NIH) and Baron Chanda (University of Wisconsin–Madison) for sharing the expression clones, as well as David E. Shaw (D. E. Shaw Research) for providing models of the KV1.2/2.1 channel in different states and Nikolay Petrosian for modelling VSD-I of NaV1.4. This work was funded, in part, by UK Medical Research Council Project Grant MR/M006948/1 (to R.M.), the Wellcome Trust (D.A.K. and D.M.K.), the Molecular and Cell Biology Program of the Russian Academy of Sciences (A.A.V. and Z.O.S.), and Russian Foundation for Basic Research Grant 16-34-01185 (to A.A.B.). NMR study was funded by Russian Science Foundation Grant 16-14-10338 (to Z.O.S.). NMR experiments were carried out using equipment provided by the core facility of the Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry (supported by Russian Ministry of Education and Science Grant RFMEFI62117X0018). Parts of this work were supported by NIH Grant R01NS091352 (to F.B.). M.G.T. was funded by an MRC Centre for Neuromuscular Diseases PhD studentship. M.G.T., M.G.H., and R.M. are supported by the University College London Hospitals Biomedical Research Centre. We dedicate this paper to the memory of Professor Eugene Grishin under whose leadership the study of Heriaeus toxins has begun.
Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.
PY - 2018/4/24
Y1 - 2018/4/24
N2 - Gating pore currents through the voltage-sensing domains (VSDs) of the skeletal muscle voltage-gated sodium channel NaV1.4 underlie hypokalemic periodic paralysis (HypoPP) type 2. Gating modifier toxins target ion channels by modifying the function of the VSDs. We tested the hypothesis that these toxins could function as blockers of the pathogenic gating pore currents. We report that a crab spider toxin Hm-3 from Heriaeus melloteei can inhibit gating pore currents due to mutations affecting the second arginine residue in the S4 helix of VSD-I that we have found in patients with HypoPP and describe here. NMR studies show that Hm-3 partitions into micelles through a hydrophobic cluster formed by aromatic residues and reveal complex formation with VSD-I through electrostatic and hydrophobic interactions with the S3b helix and the S3–S4 extracellular loop. Our data identify VSD-I as a specific binding site for neurotoxins on sodium channels. Gating modifier toxins may constitute useful hits for the treatment of HypoPP.
AB - Gating pore currents through the voltage-sensing domains (VSDs) of the skeletal muscle voltage-gated sodium channel NaV1.4 underlie hypokalemic periodic paralysis (HypoPP) type 2. Gating modifier toxins target ion channels by modifying the function of the VSDs. We tested the hypothesis that these toxins could function as blockers of the pathogenic gating pore currents. We report that a crab spider toxin Hm-3 from Heriaeus melloteei can inhibit gating pore currents due to mutations affecting the second arginine residue in the S4 helix of VSD-I that we have found in patients with HypoPP and describe here. NMR studies show that Hm-3 partitions into micelles through a hydrophobic cluster formed by aromatic residues and reveal complex formation with VSD-I through electrostatic and hydrophobic interactions with the S3b helix and the S3–S4 extracellular loop. Our data identify VSD-I as a specific binding site for neurotoxins on sodium channels. Gating modifier toxins may constitute useful hits for the treatment of HypoPP.
KW - Channelopathy
KW - Gating modifier
KW - Hypokalemic periodic paralysis
KW - Neurotoxin
KW - Sodium channel
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U2 - 10.1073/pnas.1720185115
DO - 10.1073/pnas.1720185115
M3 - Article
C2 - 29636418
AN - SCOPUS:85045910164
VL - 115
SP - 4495
EP - 4500
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 17
ER -