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A tamoxifen receptor within a voltage-gated sodium channel.
<div class='caption-title'>Overview of crystal structures of the NavMs sodium channel complexes with tamoxifen or its metabolic products</div>
<div class='caption-title'>Comparisons of NavMs structures in the absence and presence of tamoxifen and its metabolites</div>
Sula A, Hollingworth D, Ng LCT, Larmore M, DeCaen PG, Wallace BA
OpenAccess logo Mol Cell 81 1160-1169.e5 (2021)
Related entries: 6sx7, 6sxc, 6sxe, 6sxf, 6sxg, 6z8c

Cited: 13 times
EuropePMC logo PMID: 33503406

Abstract

Voltage-gated sodium channels are targets for many analgesic and antiepileptic drugs whose therapeutic mechanisms and binding sites have been well characterized. We describe the identification of a previously unidentified receptor site within the NavMs voltage-gated sodium channel. Tamoxifen, an estrogen receptor modulator, and its primary and secondary metabolic products bind at the intracellular exit of the channel, which is a site that is distinct from other previously characterized sodium channel drug sites. These compounds inhibit NavMs and human sodium channels with similar potencies and prevent sodium conductance by delaying channel recovery from the inactivated state. This study therefore not only describes the structure and pharmacology of a site that could be leveraged for the development of new drugs for the treatment of sodium channelopathies but may also have important implications for off-target health effects of this widely used therapeutic drug.

Articles - 6sx5 mentioned but not cited (1)

  1. A tamoxifen receptor within a voltage-gated sodium channel. Sula A, Hollingworth D, Ng LCT, Larmore M, DeCaen PG, Wallace BA. Mol Cell 81 1160-1169.e5 (2021)


Reviews citing this publication (4)

  1. The Interface of Nuclear and Membrane Steroid Signaling. Treviño LS, Gorelick DA. Endocrinology 162 bqab107 (2021)
  2. Cannabidiol and Sodium Channel Pharmacology: General Overview, Mechanism, and Clinical Implications. Ghovanloo MR, Ruben PC. Neuroscientist 28 318-334 (2022)
  3. Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers. Masi M, Racchi M, Travelli C, Corsini E, Buoso E. Cells 10 2999 (2021)
  4. Combinatorial Therapy of Cancer: Possible Advantages of Involving Modulators of Ionic Mechanisms. Djamgoz MBA. Cancers (Basel) 14 2703 (2022)

Articles citing this publication (8)

  1. Characterization in Inhibitory Effectiveness of Carbamazepine in Voltage-Gated Na+ and Erg-Mediated K+ Currents in a Mouse Neural Crest-Derived (Neuro-2a) Cell Line. Wu PM, Cho HY, Chiang CW, Chuang TH, Wu SN, Tu YF. Int J Mol Sci 23 7892 (2022)
  2. An open state of a voltage-gated sodium channel involving a π-helix and conserved pore-facing asparagine. Choudhury K, Kasimova MA, McComas S, Howard RJ, Delemotte L. Biophys J 121 11-22 (2022)
  3. A Novel Quantitative Electrocardiography Strategy Reveals the Electroinhibitory Effect of Tamoxifen on the Mouse Heart. Xie M, Zhu S, Liu G, Wu Y, Zhou W, Yu D, Wan J, Xing S, Wang S, Gan L, Li G, Chang D, Lai H, Liu N, Zhu P. J Cardiovasc Transl Res 16 1232-1248 (2023)
  4. An α-π transition in S6 shapes the conformational cycle of the bacterial sodium channel NavAb. Choudhury K, Howard RJ, Delemotte L. J Gen Physiol 155 e202213214 (2023)
  5. Effective Modulation by Lacosamide on Cumulative Inhibition of INa during High-Frequency Stimulation and Recovery of INa Block during Conditioning Pulse Train. Wu PM, Lin YC, Chiang CW, Cho HY, Chuang TH, Yu MC, Wu SN, Tu YF. Int J Mol Sci 23 11966 (2022)
  6. Small molecule modulation of the Drosophila Slo channel elucidated by cryo-EM. Raisch T, Brockmann A, Ebbinghaus-Kintscher U, Freigang J, Gutbrod O, Kubicek J, Maertens B, Hofnagel O, Raunser S. Nat Commun 12 7164 (2021)
  7. Targeting the tamoxifen receptor within sodium channels to block osteoarthritic pain. McCollum MM, Larmore M, Ishihara S, Ng LCT, Kimura LF, Guadarrama E, Ta MC, Vien TN, Frost GB, Scheidt KA, Miller RE, DeCaen PG. Cell Rep 40 111248 (2022)
  8. Protein structure, dynamics, and function-a 20th IUPAB Congress symposium. Garratt RC. Biophys Rev 13 867-869 (2021)


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