Abstract
Voltage-gated sodium (NaV) channels are transmembrane proteins that initiate and propagate neuronal and cardiac action potentials. NaV channel β subunits have been widely studied due to their modulatory role. Mice null for Scn1b, which encodes NaV β1 and β1b subunits, have defects in neuronal development and excitability, spontaneous generalized seizures, cardiac arrhythmias, and early mortality. A mutation in exon 3 of SCN1B, c.308A>T leading to β1_p.D103V and β1b_p.D103V, was previously found in a patient with a history of proarrhythmic conditions with progressive atrial standstill as well as cognitive and motor deficits accompanying structural brain abnormalities. We investigated whether β1 or β1b subunits carrying this mutation affect NaV1.5 and/or NaV1.1 currents using a whole cell patch-clamp technique in tsA201 cells. We observed a decrease in sodium current density in cells co-expressing NaV1.5 or NaV1.1 and β1D103V compared to β1WT. Interestingly, β1bD103V did not affect NaV1.1 sodium current density but induced a positive shift in the voltage dependence of inactivation and a faster recovery from inactivation compared to β1bWT. The β1bD103V isoform did not affect NaV1.5 current properties. Although the SCN1B_c.308A>T mutation may not be the sole cause of the patient’s symptoms, we observed a clear loss of function in both cardiac and brain sodium channels. Our results suggest that the mutant β1 and β1b subunits play a fundamental role in the observed electrical dysfunction.
Highlights
Voltage-gated sodium (NaV) channels are transmembrane proteins that initiate and propagate neuronal and cardiac action potentials (Catterall, 2000; Catterall et al, 2005)
This mutation results in an amino acid change from a hydrophilic aspartic acid to a hydrophobic valine at position 103 (p.D103V) of the sodium channel auxiliary β subunit
D103 is probably important to channel function, as it is highly conserved among all sodium channel β subunits, except for β4, and is conserved among different species (Figures 1A,B)
Summary
Voltage-gated sodium (NaV) channels are transmembrane proteins that initiate and propagate neuronal and cardiac action potentials (Catterall, 2000; Catterall et al, 2005). These channels have an α subunit composed of four domains (DI–DIV), each with six transmembrane segments (S1–S6). All β subunits with the exception of β1b are composed of an extracellular N-terminal immunoglobulin-like (Ig) domain (ECD), a transmembrane region, and an intracellular C-terminal domain (Brackenbury and Isom, 2011). Similar to the other β subunits, β1b is composed of an N-terminal region encoded by exons 1–3 of SCN1B. It is predicted to have the same cellular interactions as the β1 subunit because it shares the same ECD (O’Malley and Isom, 2016)
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