|Authors||L. Yuan, J. Koivumäki, B. Liang, L. G. Lorentzen, J. H. Svendsen, J. Tfelt-Hansen, M. Maleckar, N. Schmitt, M. S. Olesen and T. Jespersen|
|Title||Investigations of the NaV\beta1b Sodium Channel Subunit in Human Ventricle; Functional Characterization of the H162P Brugada Syndrome Mutant|
|Afilliation||, Scientific Computing, Scientific Computing|
|Project(s)||Center for Biomedical Computing (SFF)|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Journal||Heart and Circulatory Physiology|
Brugada Syndrome (BrS) is a rare inherited disease which can give rise to ventricular arrhythmia and ultimately sudden cardiac death. Numerous loss-of-function mutations in the cardiac sodium channel NaV1.5 have been associated with BrS. However, few mutations in the auxiliary NaV\beta1-4 subunits have been linked to this disease. Here we investigate differences in expression and function between NaV\beta1 and NaV\beta1b, and whether the H162P/NaV\beta1b mutation found in a BrS patient is likely to be the underlying cause of disease. The impact of NaV\beta1-subunits were investigated by patch-clamp electrophysiology and the obtained in vitro values were used for subsequent in silico modeling. We find that NaV\beta1b transcripts are expressed at higher levels than NaV\beta1 transcripts in the human heart. NaV\beta1 and NaV\beta1b co-expressed with NaV1.5 show similar kinetics, but the current level of NaV\beta1b was higher. When co-expressed with NaV1.5, the NaV\beta1b/H162P mutated subunit peak current density was reduced by 47% (-626.5\pm89 vs. - 333.5\pm71 pA/pF), V½ steady-state inactivation shifted by -8.7 mV (-70.2\pm1.9 vs. -77.0\pm2.3 mV), and time-dependent recovery from inactivation slowed by more than 50% as compared to co-expression with NaV\beta1b WT. Computer simulations revealed that these electrophysiological changes result in a reduction in both action potential amplitude and maximum upstroke velocity. The experimental data thereby indicate that NaV\beta1b/H162P results in reduced sodium channel activity functionally effecting the ventricular action potential. This result is an important replication to support the notion that BrS can be linked to the function of NaV\beta1b and is associated with loss-of-function of the cardiac sodium channel.