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The Journal of Neuroscience, March 30, 2005, 25(13):3341-3349; doi:10.1523/JNEUROSCI.0104-05.2005

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

Massimo Mantegazza,^1,2 * Frank H. Yu,^1 * Andrew J. Powell,³ Jeffrey J. Clare,³ William A. Catterall,¹ and Todd Scheuer¹

¹Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington 98195-7280, ²Department of Neurophysiology, Istituto Neurologico Besta, 20126 Milan, Italy, and ³Department of Gene Expression and Protein Biochemistry, GlaxoSmithKline, Stevenage, Herts SG1 2NY, United Kingdom

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_NaP, has been implicated in integrative functions of neurons including threshold for firing, neuronal bursting, and signal integration. G-protein subunits increase I_NaP, but the sodium channel subtypes that conduct I_NaP and the target site(s) on the sodium channel molecule required for modulation by G are poorly defined. Here, we show that I_NaP conducted by Na_v1.1 and Na_v1.2 channels (Na_v1.1 > Na_v1.2) is modulated by G; Na_v1.4 and Na_v1.5 channels produce smaller I_NaP that is not regulated by G. These qualitative differences in modulation by G 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. However, the C-terminal domains determine the quantitative extent of modulation of Na_v1.2 channels by G. Studies of chimeric and truncated Na_v1.2 channels identify molecular determinants that affect modulation of I_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 when attached to the proximal C-terminal domain. Our results further define the sodium channel subtypes that generate I_NaP and identify crucial molecular determinants in the C-terminal domain required for modulation by G when attached to the transmembrane body of a responsive sodium channel.

Key words: sodium; channels; G-proteins; inactivation; neuromodulation; excitability

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Received Aug 16, 2004; accepted January 27, 2005.

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