The intracellular segment of the sodium channel β1 subunit is required for its efficient association with the channel α subunit

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Abstract
Sodium channels consist of a pore-forming α subunit and auxiliary β1 and β2 subunits. The subunit β1 alters the kinetics and voltage-dependence of sodium channels expressed in Xenopus oocytes or mammalian cells. Functional modulation in oocytes depends on specific regions in the N-terminal extracellular domain of β1, but does not require the intracellular C-terminal domain. Functional modulation is qualitatively different in mammalian cells, and thus could involve different molecular mechanisms. As a first step toward testing this hypothesis, we examined modulation of brain NaV1.2a sodium channel α subunits expressed in Chinese hamster lung cells by a mutant β1 construct with 34 amino acids deleted from the C-terminus. This deletion mutation did not modulate sodium channel function in this cell system. Co-immunoprecipitation data suggest that this loss of functional modulation was caused by inefficient association of the mutant β1 with α, despite high levels of expression of the mutant protein. In Xenopus oocytes, injection of approximately 10 000 times more mutant β1 RNA was required to achieve the level of functional modulation observed with injection of full-length β1. Together, these findings suggest that the C-terminal cytoplasmic domain of β1 is an important determinant of β1 binding to the sodium channel α subunit in both mammalian cells and Xenopus oocytes.