TY - JOUR
T1 - Absence of Functional Nav1.8 Channels in Non-diseased Atrial and Ventricular Cardiomyocytes
AU - Casini, Simona
AU - Marchal, Gerard A.
AU - Kawasaki, Makiri
AU - Nariswari, Fransisca A.
AU - Portero, Vincent
AU - Guan, Kaomei
AU - Driessen, Antoine H. G.
AU - Veldkamp, Marieke W.
AU - Mengarelli, Isabella
AU - de Groot, Joris R.
AU - Verkerk, Arie O.
AU - Remme, Carol Ann
AU - van den Berg, Nicoline W. E.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Purpose: Several studies have indicated a potential role for SCN10A/NaV1.8 in modulating cardiac electrophysiology and arrhythmia susceptibility. However, by which mechanism SCN10A/NaV1.8 impacts on cardiac electrical function is still a matter of debate. To address this, we here investigated the functional relevance of NaV1.8 in atrial and ventricular cardiomyocytes (CMs), focusing on the contribution of NaV1.8 to the peak and late sodium current (INa) under normal conditions in different species. Methods: The effects of the NaV1.8 blocker A-803467 were investigated through patch-clamp analysis in freshly isolated rabbit left ventricular CMs, human left atrial CMs and human-induced pluripotent stem cell-derived CMs (hiPSC-CMs). Results: A-803467 treatment caused a slight shortening of the action potential duration (APD) in rabbit CMs and hiPSC-CMs, while it had no effect on APD in human atrial cells. Resting membrane potential, action potential (AP) amplitude, and AP upstroke velocity were unaffected by A-803467 application. Similarly, INa density was unchanged after exposure to A-803467 and NaV1.8-based late INa was undetectable in all cell types analysed. Finally, low to absent expression levels of SCN10A were observed in human atrial tissue, rabbit ventricular tissue and hiPSC-CMs. Conclusion: We here demonstrate the absence of functional NaV1.8 channels in non-diseased atrial and ventricular CMs. Hence, the association of SCN10A variants with cardiac electrophysiology observed in, e.g. genome wide association studies, is likely the result of indirect effects on SCN5A expression and/or NaV1.8 activity in cell types other than CMs.
AB - Purpose: Several studies have indicated a potential role for SCN10A/NaV1.8 in modulating cardiac electrophysiology and arrhythmia susceptibility. However, by which mechanism SCN10A/NaV1.8 impacts on cardiac electrical function is still a matter of debate. To address this, we here investigated the functional relevance of NaV1.8 in atrial and ventricular cardiomyocytes (CMs), focusing on the contribution of NaV1.8 to the peak and late sodium current (INa) under normal conditions in different species. Methods: The effects of the NaV1.8 blocker A-803467 were investigated through patch-clamp analysis in freshly isolated rabbit left ventricular CMs, human left atrial CMs and human-induced pluripotent stem cell-derived CMs (hiPSC-CMs). Results: A-803467 treatment caused a slight shortening of the action potential duration (APD) in rabbit CMs and hiPSC-CMs, while it had no effect on APD in human atrial cells. Resting membrane potential, action potential (AP) amplitude, and AP upstroke velocity were unaffected by A-803467 application. Similarly, INa density was unchanged after exposure to A-803467 and NaV1.8-based late INa was undetectable in all cell types analysed. Finally, low to absent expression levels of SCN10A were observed in human atrial tissue, rabbit ventricular tissue and hiPSC-CMs. Conclusion: We here demonstrate the absence of functional NaV1.8 channels in non-diseased atrial and ventricular CMs. Hence, the association of SCN10A variants with cardiac electrophysiology observed in, e.g. genome wide association studies, is likely the result of indirect effects on SCN5A expression and/or NaV1.8 activity in cell types other than CMs.
KW - Cardiomyocytes
KW - Late sodium current
KW - Patch-clamp
KW - SCN10A/Na 1.8
KW - Sodium channel
KW - hiPSC-CMs
UR - http://www.scopus.com/inward/record.url?scp=85077583277&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s10557-019-06925-6
DO - https://doi.org/10.1007/s10557-019-06925-6
M3 - Article
C2 - 31916131
SN - 0920-3206
VL - 33
SP - 649
EP - 660
JO - Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy
JF - Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy
IS - 6
ER -