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4-Chloro-3-nitro-N-butylbenzenesulfonamide acts on KV3.1 channels by an open-channel blocker mechanism

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Abstract

The effects of 4-chloro-3-nitro-N-butylbenzenesulfonamide (SMD2) on KV3.1 channels, heterologous expressed in L-929 cells, were studied with the whole cell patch-clamp technique. SMD2 blocks KV3.1 in a reversible and use-dependent manner, with IC50 around 10 µM, and a Hill coefficient around 2. Although the conductance vs. voltage relationship in control condition can be described by a single Boltzmann function, two terms are necessary to describe the data in the presence of SMD2. The activation and deactivation time constants are weakly voltage dependent both for control and in the presence of SMD2. SMD2 does not change the channel selectivity and tail currents show a typical crossover phenomenon. The time course of inactivation has a fast and a slow component, and SMD2 significantly decreased their values. Steady-state inactivation is best described by a Boltzmann equation with V 1/2 (the voltage where the probability to find the channels in the inactivated state is 50%) and K (slope factor) equals to −22.9 ± 1.5 mV and 5.3 ± 0.9 mV for control, and −30.3 ± 1.3 mV and 6 ± 0.8 mV for SMD2, respectively. The action of SMD2 is enhanced by high frequency stimulation, and by the time the channel stays open. Taken together, our results suggest that SMD2 blocks the open conformation of KV3.1. From a pharmacological and therapeutic point of view, N-alkylsulfonamides may constitute a new class of pharmacological modulators of KV3.1.

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  • 12 October 2017

    Unfortunately, grey trace on Figure 2c was missing in the original publication of the article.

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Acknowledgements

We are thankful to MSc Carina Couto Martins for synthesis of benzenesulfonamide, to Dr. André Dagostin and Fernando Aguiar for technical assistance; Dr. Dario Zamboni for providing us the wild type L929 cells and Dr. Ricardo Mauricio Leão and Davi Moraes for lab facilities. This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-CAPES (PhD fellowship-Carlos Alberto Zanutto Bassetto Jr.) and Fundação de Amparo à Pesquisa do Estado de São Paulo-FAPESP for research funding of Professors Wamberto Antonio Varanda (2012/19750-7) and Eduardo René Pérez. González (2013/24487-6), respectively.

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Authors and Affiliations

  1. Fine Organic Chemistry Laboratory, Department of Chemistry and Biochemistry, Faculty of Science and Technology, São Paulo State University (Unesp)-Campus of Presidente Prudente, Presidente Prudente, SP, Brazil

    Carlos Alberto Zanutto Bassetto Junior & Eduardo René Pérez González

  2. Post-Graduate Program in Science and Material Technology, Presidente Prudente, SP, Brazil

    Carlos Alberto Zanutto Bassetto Junior & Eduardo René Pérez González

  3. Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil

    Wamberto Antonio Varanda

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  1. Carlos Alberto Zanutto Bassetto Junior
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Correspondence to Carlos Alberto Zanutto Bassetto Junior.

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Handling Editor: E. I. Closs.

A correction to this article is available online at https://doi.org/10.1007/s00726-017-2504-4.

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Bassetto Junior, C.A.Z., Varanda, W.A. & González, E.R.P. 4-Chloro-3-nitro-N-butylbenzenesulfonamide acts on KV3.1 channels by an open-channel blocker mechanism. Amino Acids 49, 1895–1906 (2017). https://doi.org/10.1007/s00726-017-2488-0

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