Subtype specificity interaction of bactridines with mammalian, insect and bacterial sodium channels under voltage clamp conditions

Authors


Correspondence

Jan Tytgat, Laboratory of Toxicology, University of Leuven (K.U. Leuven), Campus Gasthuisberg O&N2, Herestraat 49, PO Box 922, B-3000 Leuven, Belgium

Fax: +32 16 3 23405

Tel: +32 16 3 23403

E-mail: Jan.Tytgat@pharm.kuleuven.be

Gina D'Suze, Laboratory on Cellular Neuropharmacology, Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, IVIC CBB, Apartado 20632, Caracas 1020A, Venezuela

Fax: +58 212 504 1093

Tel: +58 212 504 1225

E-mail: gdsuze@ivic.gob.ve; gina.dsuze@gmail.com

Abstract

The present work demonstrates that bactridines (Bacts) possess different selectivities for neuronal and muscular voltage-dependent sodium (NaV) channels, with subtle differences on channel isoforms. Bacts 2, 3, 4, 5 and 6 (100 nm) reduced the peak current of several skeletal and neuronal channel isoforms selectively. Bacts 2 and 3 were more potent on NaV1.4, Bacts 4 and 6 on NaV1.3 and Bact 5 on NaV1.7. Bactridines (except Bacts 1 and 5) caused a hyperpolarizing shift in the V1/2 of activation and inactivation of NaV1.3, NaV1.4 and NaV1.6. Voltage shifts of Boltzmann curves fitted to activation and inactivation occurred with a decrease in κ. Since the slope is proportional to κ = RT/zF, changes in κ probably express changes in z, the valence, in a voltage-dependent manner. Changes in z may express toxin-induced changes in the channel ionic environment, perhaps due to surface charges of the molecules. Bact 2 induced a NaV1.2 voltage shift of the activation curves but no shift of the mutant NaV1.2 IFM/QQQ; peak INa was reduced in both channel forms, suggesting that channel blockage resulted from toxin binding to a site partially distinct from the α subunit binding site 4. Bactridines emerge as potential research tools to understand sodium channel isoform structure–function relationships and also as pharmacologically interesting peptides.

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