Modulation of Na(v)1.5 by beta1-- and beta3-subunit co-expression in mammalian cells

Cardiac sodium channels (Na(v)1.5) comprise a pore-forming alpha-subunit and auxiliary beta-subunits that modulate channel function. In the heart, beta1 is expressed throughout the atria and ventricles, whilst beta3 is present only in the ventricles and Purkinje fibers. In view of this expression pattern, we determined the effects of beta3 and beta1 co-expression alone, and in combination, on Na(v)1.5 stably expressed in Chinese hamster ovary cells. The current/voltage relationship was shifted -5 mV with either beta1 or beta3 co-expression alone and -10 mV with co-expression of both beta1 and beta3. In addition, beta3 and beta1/beta3 co-expression accelerated macroscopic current decay. There were significant hyperpolarizing shifts in equilibrium gating relationships with co-expression of beta1 and beta3 alone and in combination. Co-expression of beta1/beta3 together resulted in a greater hyperpolarizing shift in channel availability, and an increase in the slopes of equilibrium gating relationships. Co-expression of beta3 and beta1/beta3, but not beta1, slowed recovery from inactivation at -90 mV. Development of inactivation at -70 and -50 mV was accelerated by beta-subunit co-expression alone and in combination. beta-Subunit co-expression also reduced the late Na current measured at 200 ms. In conclusion, beta-subunits modulate Na(v)1.5 gating with important differences between co-expression of beta1 and beta3 alone and beta1/beta3 together.