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

• Published in: The Journal of neuroscience Vol. 25; no. 13; pp. 3341 - 3349
• Main Authors: Mantegazza, Massimo, Yu, Frank H, Powell, Andrew J, Clare, Jeffrey J, Catterall, William A, Scheuer, Todd
• Format: Journal Article
• Language: English
• Published: 30.03.2005
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.0104-05.2005

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, I sub(NaP), has been implicated in integrative functions of neurons including threshold for firing, neuronal bursting, and signal integration. G-protein beta gamma subunits increase I sub(NaP), but the sodium channel subtypes that conduct I sub(NaP) and the target site(s) on the sodium channel molecule required for modulation by G beta gamma are poorly defined. Here, we show that I sub(NaP) conducted by Na sub(v)1.1 and Na sub(v)1.2 channels (Na sub(v)1.1 > Na sub(v)1.2) is modulated by G beta gamma ; Na sub(v)1.4 and Na sub(v)1.5 channels produce smaller I sub(NaP) that is not regulated by G beta gamma . These qualitative differences in modulation by G beta gamma 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 G beta gamma . However, the C-terminal domains determine the quantitative extent of modulation of Na sub(v)1.2 channels by G beta gamma . Studies of chimeric and truncated Na sub(v)1.2 channels identify molecular determinants that affect modulation of I sub(NaP) located 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 G beta gamma when attached to the proximal C-terminal domain. Our results further define the sodium channel subtypes that generate I sub(NaP) and identify crucial molecular determinants in the C-terminal domain required for modulation by G beta gamma when attached to the transmembrane body of a responsive sodium channel.