Investigations of the Navβ1b sodium channel subunit in human ventricle; functional characterization of the H162P Brugada Syndrome mutant
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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 Navβ1-4 subunits have been linked to this disease. Here we investigated differences in expression and function between Navβ1 and Navβ1b, and whether the H162P/Navβ1b mutation found in a BrS patient is likely to be the underlying cause of disease. The impact of Navβ-subunits were investigated by patch-clamp electrophysiology and the obtained in vitro values were used for subsequent in silico modeling. We found that Navβ1b transcripts were expressed at higher levels than Navβ1 transcripts in the human heart. Navβ1b was found to increase the current level when co-expressed with Nav1.5, the Navβ1b/H162P mutated subunit peak current density was reduced by 48 % (-645±151 vs - 334±71 pA/pF), V1/2 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 more than 50% as compared to co-expression with Navβ1b WT. 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 Navβ1b/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 Navβ1b and is associated with loss-of-function of the cardiac sodium channel.
|Tidsskrift||American Journal of Physiology: Heart and Circulatory Physiology|
|Status||Udgivet - 21 feb. 2014|