Background: Voltage-gated sodium channels are functionally expressed in human carcinomas. In breast and colon cancers, the neonatal splice variant of Nav1.5 (nNav1.5) is dominant. This differs from the adult (aNav1.5) by several amino acids, including an outer charge reversal (residue-211): negatively charged aspartate (aNav1.5) versus positively charged lysine (nNav1.5). Thus, nNav1.5 and aNav1.5 may respond to extracellular charges differently. Materials and Methods: We used whole-cell patch-clamp recording to compare the electrophysiological effects of the monovalent cation hydrogen (H+) on nNav1.5 and aNav1.5 expressed stably in EBNA cells. Results: Increasing the H+ concentration (acidifying pH) reduced channel conductance and inhibited peak currents. Also, there was a positive shift in the voltage dependence of activation. These changes were significantly smaller for nNav1.5, compared with aNav1.5. Conclusions: nNav1.5 was more resistant to the suppressive effects of acidification compared with aNav1.5. Thus, nNav1.5 may have an advantage in promoting metastasis from the acidified tumor microenvironment.
Keywords: H+; Nav1.5; alternative splicing; breast cancer; cardiac muscle; neonatal; pH.
Copyright 2019, Mary Ann Liebert, Inc., publishers.