Investigations of the Na v β1b sodium channel subunit in human ventricle; functional characterization of the H162P Brugada syndrome mutant

• Published in: American journal of physiology. Heart and circulatory physiology 2014-04, Vol.306 (8), p.H1204-H1212
• Main Authors: Yuan, Lei, Koivumäki, Jussi T., Liang, Bo, Lorentzen, Lasse G., Tang, Chuyi, Andersen, Martin N., Svendsen, Jesper H., Tfelt-Hansen, Jacob, Maleckar, Molly, Schmitt, Nicole, Olesen, Morten S., Jespersen, Thomas
• Format: Article
• Language: English
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00405.2013

Brugada syndrome (BrS) is a rare inherited disease that can give rise to ventricular arrhythmia and ultimately sudden cardiac death. Numerous loss-of-function mutations in the cardiac sodium channel Na v 1.5 have been associated with BrS. However, few mutations in the auxiliary Na v β1–4 subunits have been linked to this disease. Here we investigated differences in expression and function between Na v β1 and Na v β1b and whether the H162P/Na v β1b mutation found in a BrS patient is likely to be the underlying cause of disease. The impact of Na v β subunits was investigated by patch-clamp electrophysiology, and the obtained in vitro values were used for subsequent in silico modeling. We found that Na v β1b transcripts were expressed at higher levels than Na v β1 transcripts in the human heart. Na v β1 and Na v β1b coexpressed with Na v 1.5 induced a negative shift on steady state of activation and inactivation compared with Na v 1.5 alone. Furthermore, Na v β1b was found to increase the current level when coexpressed with Na v 1.5, Na v β1b/H162P mutated subunit peak current density was reduced by 48% (−645 ± 151 vs. −334 ± 71 pA/pF), V 1/2 steady-state inactivation shifted by −6.7 mV (−70.3 ± 1.5 vs. −77.0 ± 2.8 mV), and time-dependent recovery from inactivation slowed by >50% compared with coexpression with Na v β1b wild type. Computer simulations revealed that these electrophysiological changes resulted in a reduction in both action potential amplitude and maximum upstroke velocity. The experimental data thereby indicate that Na v β1b/H162P results in reduced sodium channel activity functionally affecting the ventricular action potential. This result is an important replication to support the notion that BrS can be linked to the function of Na v β1b and is associated with loss-of-function of the cardiac sodium channel.