Differential effects of modified batrachotoxins on voltage-gated sodium channel fast and slow inactivation

Tim M G MacKenzie; Fayal Abderemane-Ali; Catherine E Garrison; Daniel L Minor Jr; J Du Bois

doi:10.1016/j.chembiol.2021.12.003

Differential effects of modified batrachotoxins on voltage-gated sodium channel fast and slow inactivation

Cell Chem Biol. 2022 Apr 21;29(4):615-624.e5. doi: 10.1016/j.chembiol.2021.12.003. Epub 2021 Dec 27.

Authors

Tim M G MacKenzie¹, Fayal Abderemane-Ali², Catherine E Garrison¹, Daniel L Minor Jr³, J Du Bois⁴

Affiliations

¹ Department of Chemistry, Stanford University, 337 Campus Drive, Stanford, CA 94305, USA.
² Cardiovascular Research Institute, University of California, San Francisco, Box 3122, 555 Mission Bay Boulevard South, Rm. 452Z, San Francisco, CA 94158-9001, USA.
³ Cardiovascular Research Institute, University of California, San Francisco, Box 3122, 555 Mission Bay Boulevard South, Rm. 452Z, San Francisco, CA 94158-9001, USA; Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158-9001, USA; California Institute for Quantitative Biomedical Research, University of California, San Francisco, CA 94158-9001, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, CA 94158-9001, USA; Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Electronic address: daniel.minor@ucsf.edu.
⁴ Department of Chemistry, Stanford University, 337 Campus Drive, Stanford, CA 94305, USA. Electronic address: jdubois@stanford.edu.

Abstract

Voltage-gated sodium channels (Na_Vs) are targets for a number of acute poisons. Many of these agents act as allosteric modulators of channel activity and serve as powerful chemical tools for understanding channel function. Herein, we detail studies with batrachotoxin (BTX), a potent steroidal amine, and three ester derivatives prepared through de novo synthesis against recombinant Na_V subtypes (rNa_V1.4 and hNa_V1.5). Two of these compounds, BTX-B and BTX-^cHx, are functionally equivalent to BTX, hyperpolarizing channel activation and blocking both fast and slow inactivation. BTX-yne-a C20-n-heptynoate ester-is a conspicuous outlier, eliminating fast but not slow inactivation. This property differentiates BTX-yne among other Na_V modulators as a unique reagent that separates inactivation processes. These findings are supported by functional studies with bacterial Na_Vs (BacNa_Vs) that lack a fast inactivation gate. The availability of BTX-yne should advance future efforts aimed at understanding Na_V gating mechanisms and designing allosteric regulators of Na_V activity.

Keywords: Na(V) fast inactivation; Na(V) slow inactivation; batrachotoxin; electrophysiology; voltage-gated sodium channels (Na(V)).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Batrachotoxins* / pharmacology
Esters
Sodium / metabolism
Voltage-Gated Sodium Channels*

Substances

Batrachotoxins
Esters
Voltage-Gated Sodium Channels
Sodium

Abstract

Publication types

MeSH terms

Substances

Grants and funding