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The Journal of Neuroscience, February 18, 2009, 29(7):2027-2042; doi:10.1523/JNEUROSCI.4531-08.2009

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Cellular/Molecular
Regulation of Persistent Na Current by Interactions between β Subunits of Voltage-Gated Na Channels

Teresa K. Aman,¹ Tina M. Grieco-Calub,¹ Chunling Chen,³ Raffaella Rusconi,³ Emily A. Slat,³ Lori L. Isom,³ and Indira M. Raman^1,2

¹Interdepartmental Neuroscience Program and ²Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, and ³Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109

Correspondence should be addressed to Indira M. Raman, Department of Neurobiology and Physiology, 2205 Tech Drive, Northwestern University, Evanston, IL 60208. Email: i-raman{at}northwestern.edu

The β subunits of voltage-gated Na channels (Scnxb) regulate the gating of pore-forming subunits, as well as their trafficking and localization. In heterologous expression systems, β1, β2, and β3 subunits influence inactivation and persistent current in different ways. To test how the β4 protein regulates Na channel gating, we transfected β4 into HEK (human embryonic kidney) cells stably expressing Na_V1.1. Unlike a free peptide with a sequence from the β4 cytoplasmic domain, the full-length β4 protein did not block open channels. Instead, β4 expression favored open states by shifting activation curves negative, decreasing the slope of the inactivation curve, and increasing the percentage of noninactivating current. Consequently, persistent current tripled in amplitude. Expression of β1 or chimeric subunits including the β1 extracellular domain, however, favored inactivation. Coexpressing Na_V1.1 and β4 with β1 produced tiny persistent currents, indicating that β1 overcomes the effects of β4 in heterotrimeric channels. In contrast, β1_C121W, which contains an extracellular epilepsy-associated mutation, did not counteract the destabilization of inactivation by β4 and also required unusually large depolarizations for channel opening. In cultured hippocampal neurons transfected with β4, persistent current was slightly but significantly increased. Moreover, in β4-expressing neurons from Scn1b and Scn1b/Scn2b null mice, entry into inactivated states was slowed. These data suggest that β1 and β4 have antagonistic roles, the former favoring inactivation, and the latter favoring activation. Because increased Na channel availability may facilitate action potential firing, these results suggest a mechanism for seizure susceptibility of both mice and humans with disrupted β1 subunits.

Key words: resurgent; Na_Vβ4; Scn4b; Scn1b; Scn1a; GEFS+; epilepsy; inactivation; Purkinje; CA3

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Received Sept. 21, 2008; revised Dec. 30, 2008; accepted Jan. 6, 2009.

Correspondence should be addressed to Indira M. Raman, Department of Neurobiology and Physiology, 2205 Tech Drive, Northwestern University, Evanston, IL 60208. Email: i-raman{at}northwestern.edu

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