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The sodium channel -subunit SCN3b modulates the kinetics of SCN5a and is expressed heterogeneously in sheep heart

Ahmed I. Fahmi, Manoj Patel *, Edward B. Stevens †, Abigail L. Fowden ‡, James Edward John III *, Kevin Lee †, Robert Pinnock †, Kevin Morgan, Antony P. Jackson and Jamie I. Vandenberg

1. Cardiac sodium channels are composed of a pore-forming -subunit, SCN5a, and one or more auxiliary -subunits. The aim of this study was to investigate the role of the recently discovered member of the -subunit family, SCN3b, in the heart.
2. Northern blot and Western blot studies show that SCN3b is highly expressed in the ventricles and Purkinje fibres but not in atrial tissue. This is in contrast to the uniform expression of SCN1b throughout the heart.
3. Co-expression of SCN3b with the cardiac-specific -subunit SCN5a in Xenopus oocytes resulted in a threefold increase in the level of functional sodium channel expression, similar to that observed when SCN1b was co-expressed with SCN5a. These results suggest that both SCN1b and SCN3b improve the efficiency with which the mature channel is targeted to the plasma membrane.
4. When measured in cell-attached oocyte macropatches, SCN3b caused a significant depolarising shift in the half-voltage of steady-state inactivation compared to SCN5a alone or SCN5a + SCN1b. The half-voltage of steady-state activation was not significantly different between SCN5a alone and SCN5a + SCN3b or SCN5a + SCN1b.
5. The rates of inactivation for SCN5a co-expressed with either subunit were not significantly different from that for SCN5a alone. However, recovery from inactivation at -90 mV was significantly faster for SCN5a + SCN1b compared to SCN5a + SCN3b, and both were significantly faster than SCN5a alone.
6. Thus, SCN1b and SCN3b have distinctive effects on the kinetics of activation and inactivation, which, in combination with the different patterns of expression of SCN3b and SCN1b, could have important consequences for the integrated electrical activity of the intact heart.

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