Open AccessCationic Modulation of Voltage-Gated Sodium Channel (Nav1.5): Neonatal Versus Adult Splice Variants—2. Divalent (Cd2+) and Trivalent (Gd3+) Ions
Author(s) -
Rustem Onkal,
Scott P. Fraser,
Mustafa B.A. Djamgoz
Publication year - 2019
Publication title -
bioelectricity
Language(s) - English
Resource type - Journals
eISSN - 2576-3113
pISSN - 2576-3105
DOI - 10.1089/bioe.2019.0014
Subject(s) - extracellular , sodium channel , divalent , splice , chemistry , biophysics , alternative splicing , electrophysiology , intracellular , hek 293 cells , linker , rna splicing , patch clamp , biochemistry , sodium , biology , medicine , gene isoform , gene , rna , receptor , computer science , operating system , organic chemistry
Background: A "neonatal" splice-form of the voltage-gated sodium channel Nav1.5 is functionally expressed in human cancers and potentiates metastatic cell behaviors. Splicing causes the replacement of 7 amino acids, including a negatively charged aspartate 211 in the "adult" Nav1.5 (aNav1.5) to a positively charged lysine in the "neonatal" (nNav1.5). These changes occur in the region surrounding the DI:S3-S4 extracellular linker. The splice variants respond differently to changes in extracellular H + and this could be of pathophysiological significance. However, how the two differentially charged splice variants would react to cations of higher valency is not known. Materials and Methods: We used patch-clamp recording to compare the electrophysiological effects of Cd 2+ and Gd 3+ on "adult" and "neonatal" Nav1.5 expressed stably in EBNA-293 cells. Several parameters were determined for the two channels and statistically compared. Results: Both cations inhibited peak I Na through reducing G max and induced a positive shift in the voltage range of activation. However, unlike Gd 3+ , Cd 2+ had only a weak effect on voltage dependence of activation, and no effect on voltage dependence of inactivation, recovery from inactivation, or the kinetics of activation/inactivation. Conclusions: The electrophysiological effects of Cd 2+ and Gd 3+ studied were essentially the same for "neonatal" and "adult" Nav1.5, although these splice variants possess differences in their external charges. In contrast, the effects of H + were shown earlier to be significantly differential. Taken together, these results suggest that limited adjustment of the charged structure of pharmacological agents could enable selective targeting of neonatal Nav1.5 associated with several cancers.