Molecular Determinants for Modulation of Persistent Sodium Current by G-Protein βγ Subunits

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Abstract
Voltage-gated sodium channels are responsible for the upstroke of the action potential in most excitable cells, and their fast inactivation is essential for controlling electrical signaling. In addition, a noninactivating, persistent component of sodium current,INaP, has been implicated in integrative functions of neurons including threshold for firing, neuronal bursting, and signal integration. G-protein βγ subunits increaseINaP, but the sodium channel subtypes that conductINaPand the target site(s) on the sodium channel molecule required for modulation by Gβγ are poorly defined. Here, we show thatINaPconducted by Nav1.1 and Nav1.2 channels (Nav1.1 > Nav1.2) is modulated by Gβγ; Nav1.4 and Nav1.5 channels produce smallerINaPthat is not regulated by Gβγ. These qualitative differences in modulation by Gβγ are determined by the transmembrane body of the sodium channels rather than their cytoplasmic C-terminal domains, which have been implicated previously in modulation by Gβγ. However, the C-terminal domains determine the quantitative extent of modulation of Nav1.2 channels by Gβγ. Studies of chimeric and truncated Nav1.2 channels identify molecular determinants that affect modulation ofINaPlocated between amino acid residue 1890 and the C terminus at residue 2005. The last 28 amino acid residues of the C terminus are sufficient to support modulation by Gβγ when attached to the proximal C-terminal domain. Our results further define the sodium channel subtypes that generateINaPand identify crucial molecular determinants in the C-terminal domain required for modulation by Gβγ when attached to the transmembrane body of a responsive sodium channel.
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