Neonatal Na 1.5 channels: pharmacological distinctiveness of a cancer-related voltage-gated sodium channel splice variant.

BACKGROUND AND PURPOSE

Voltage-gated sodium (Na ) channels are expressed de novo in carcinomas where their activity promotes invasiveness. Breast and colon cancer cells express the neonatal splice variant of Na 1.5 (nNa 1.5), which has several amino acid substitutions in the domain I voltage-sensor compared with its adult counterpart (aNa 1.5). This study aimed to determine whether nNa 1.5 channels could be distinguished pharmacologically from aNa 1.5 channels.

EXPERIMENTAL APPROACH

Cells expressing either nNa 1.5 or aNa 1.5 channels were exposed to low MW inhibitors, an antibody or natural toxins, and changes in electrophysiological parameters were measured. Stable expression in EBNA cells and transient expression in Xenopus laevis oocytes were used. Currents were recorded by whole-cell patch clamp and two-electrode voltage-clamp, respectively.

KEY RESULTS

Several clinically used blockers of Na channels (lidocaine, procaine, phenytoin, mexiletine, ranolazine, and riluzole) could not distinguish between nNa 1.5 or aNa 1.5 channels. However, two tarantula toxins (HaTx and ProTx-II) and a polyclonal antibody (NESOpAb) preferentially inhibited currents elicited by either nNa 1.5 or aNa 1.5 channels by binding to the spliced region of the channel. Furthermore, the amino acid residue at position 211 (aspartate in aNa 1.5/lysine in nNa 1.5), that is, the charge reversal in the spliced region of the channel, played a key role in the selectivity, especially in antibody binding.

CONCLUSION AND IMPLICATIONS

We conclude that the cancer-related nNa 1.5 channel can be distinguished pharmacologically from its nearest neighbour, aNa 1.5 channels. Thus, it may be possible to design low MW compounds as antimetastatic drugs for non-toxic therapy of nNa 1.5-expressing carcinomas.

© 2021 The British Pharmacological Society.