%0 Journal Article %A Julliane Vasconcelos Joviano-Santos %A Artur Santos-Miranda %A Jaqueline Oliveira Sarmento %A Danilo Roman-Campos %T Ethnic-related SCN5A polymorphisms shape the in vitro pharmacological action of amiodarone upon Nav1.5 %D 2021 %R 10.1124/molpharm.120.000176 %J Molecular Pharmacology %P MOLPHARM-AR-2020-000176 %X Nav1.5-derived Na+ current (INa) exerts a pivotal role in the depolarization phase of cardiomyocytes' action potential, and therefore, changes in INa can contribute to fatal arrhythmias. Nav1.5 displays naturally occurring ethnic-related polymorphisms, which might alter the functioning and pharmacology of the channel. Some studies have shown how single nucleotide polymorphism can change the response to antiarrhythmic drugs. Investigations on the role of Nav1.5 in arrhythmogenesis, associated with its functional polymorphisms, are currently growing, as well as the possible variability in the antiarrhythmic pharmacotherapy among ethnic-groups. The influence of the ethnic-related polymorphisms (S524Y, S1103Y, R1193Q, V1951L) on the responsiveness, selectivity, and pharmacological efficacy of the clinically used antiarrhythmic, amiodarone (AMIO), is not completely known. Our objectives were to analyze biophysical and pharmacological aspects of four ethnic-related polymorphisms before and after exposure to AMIO. Polymorphisms caused reduced AMIO potency compared to wild-type (WT) that can vary up to 4x between them. AMIO shifted the voltage dependency for current inactivation, without significant effect in voltage-dependent activation to a similar extend in WT and polymorphisms. The recovery from inactivation was altered between the polymorphisms when compared to WT. Finally, the use-dependency of AMIO differed between studied groups, especially at a more depolarized cell membrane. Thus, our work may guide future studies focusing on the efficiency of AMIO in treating different arrhythmias and to establish more individualized guidelines for its use depending on the Nav1.5-polymorphism, after validating our findings using in vivo studies. Significance Statement SCN5A gene encodes the alpha subunit of Nav1.5, the main cardiac voltage-gated Na+ channel. Interestingly, ethnic-related polymorphisms are found in SCN5A. Amiodarone is used in clinical practice and some of its effects are attributed to interaction with Nav1.5. Important, amiodarone efficacy is variable among patients. Here we show that Ethnic-related SCN5A polymorphisms lead to altered Nav1.5-amiodarone interaction, which may be the cause for the variable efficacy observed in clinical usage of amiodarone. %U https://molpharm.aspetjournals.org/content/molpharm/early/2021/04/06/molpharm.120.000176.full.pdf