Neonatal Na_V1.5 channels: pharmacological distinctiveness of a cancer‐related voltage‐gated sodium channel splice variant

Abstract

Background and Purpose: Voltage-gated sodium (Na V ) channels are expressed de novo in carcinomas where their activity promotes invasiveness. Breast and colon cancer cells express the neonatal splice variant of Na V 1.5 (nNa V 1.5), which has several amino acid substitutions in the domain I voltage-sensor compared with its adult counterpart (aNa V 1.5). This study aimed to determine whether nNa V 1.5 channels could be distinguished pharmacologically from aNa V 1.5 channels.Experimental Approach: Cells expressing either nNa V 1.5 or aNa V 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 V channels (lidocaine, procaine, phenytoin, mexiletine, ranolazine, and riluzole) could not distinguish between nNa V 1.5 or aNa V 1.5 channels. However, two tarantula toxins (HaTx and ProTx-II) and a polyclonal antibody (NESOpAb) preferentially inhibited currents elicited by either nNa V 1.5 or aNa V 1.5 channels by binding to the spliced region of the channel. Furthermore, the amino acid residue at position 211 (aspartate in aNa V 1.5/lysine in nNa V 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 V 1.5 channel can be distinguished pharmacologically from its nearest neighbour, aNa V 1.5 channels. Thus, it may be possible to design low MW compounds as antimetastatic drugs for non-toxic therapy of nNa V 1.5-expressing carcinomas.

potencial uso do riluzole no tratamento do câncer

“…Este estudo demonstra um mecanismo de ação do riluzole na indução da apoptose em células de osteossarcoma. Fraser et al (2021) 87…”

“…Outro estudo com melanoma demonstrou que o riluzole induz o aumento da fosforilação de ligação smad, do lançamento de inibição do glutamato desencadeando seu acúmulo intracelular e inibindo o crescimento das células do tumor no espaço intersticial 35 . Em 2021, pesquisas apontam que o riluzole foi escolhido como potencial alvo terapêutico principalmente no controle imunológico contra câncer de mama e glioblastoma 84,85,87,88 .…”

Discovering the Triad between Nav1.5, Breast Cancer, and the Immune System: A Fundamental Review and Future Perspectives

“…The amino acid sequence in the extracellular loop in VSD1 (D1:S3–S4) of nNaV1.5 is unique and would be expected to be highly antigenic [ 166 ]. Recently, the natural immunogenicity of nNav1.5 was reported via the detection of circulating antibodies against nNav1.5 (hereafter referred to as anti-nNav1.5-Ab) [ 77 ].…”

Ranolazine: An Old Drug with Emerging Potential; Lessons from Pre-Clinical and Clinical Investigations for Possible Repositioning

“…Cancer cells expressed functional voltage-gated Na channels playing a significant role in disease progression in the prostate, breast, lung cancers, and leukemia [191]. Thus, the expression of Na v channels in tumor cells questions their role in cancer therapy and opens perspectives for a potential new target in oncology [191][192][193]. Indeed, Na v 1.7, Na v 1.6, and Na v 1.5's functional expression are associated with invasive properties of some cancer cell lines [191].…”