Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Nov 6;109(45):18577-82.
doi: 10.1073/pnas.1209142109. Epub 2012 Oct 22.

Modulation of voltage-gated K+ channels by the sodium channel β1 subunit

Hai M Nguyen  1 , Haruko Miyazaki, Naoto Hoshi, Brian J Smith, Nobuyuki Nukina, Alan L Goldin, K George Chandy
Affiliations

Modulation of voltage-gated K+ channels by the sodium channel β1 subunit

Hai M Nguyen et al. Proc Natl Acad Sci U S A. .

Abstract

Voltage-gated sodium (Na(V)) and potassium (K(V)) channels are critical components of neuronal action potential generation and propagation. Here, we report that Na(V)β1 encoded by SCN1b, an integral subunit of Na(V) channels, coassembles with and modulates the biophysical properties of K(V)1 and K(V)7 channels, but not K(V)3 channels, in an isoform-specific manner. Distinct domains of Na(V)β1 are involved in modulation of the different K(V) channels. Studies with channel chimeras demonstrate that Na(V)β1-mediated changes in activation kinetics and voltage dependence of activation require interaction of Na(V)β1 with the channel's voltage-sensing domain, whereas changes in inactivation and deactivation require interaction with the channel's pore domain. A molecular model based on docking studies shows Na(V)β1 lying in the crevice between the voltage-sensing and pore domains of K(V) channels, making significant contacts with the S1 and S5 segments. Cross-modulation of Na(V) and K(V) channels by Na(V)β1 may promote diversity and flexibility in the overall control of cellular excitability and signaling.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Activation kinetics at +40 mV (A, gray hatched area in pulse protocol represents first 30 ms analyzed), voltage dependence of activation (B) (mean ± SEM), and deactivation (C, gray hatched area in pulse protocol represents last 10 ms analyzed) of KV1.2 channels expressed in Xenopus oocytes in the presence or absence of NaVβ1 (n ≥ 7). Only currents of comparable amplitude between channel-alone, channel plus NaVβ1, were selected for analysis. (D) KV1.2 stably expressed in L929 fibroblasts exhibits use-dependent activation when repetitive depolarizing pulses at +40mV are administered at 1-s intervals. Average normalized current traces show NaVβ1 speeds up activation of KV1.2 at the first pulse and to a lesser extent at the ninth pulse (KV1.2, n = 6; KV1.2 + NaVβ1, n = 9 cells). (E) Western blot of coprecipitation experiment in transfected HEK cells showing that KV1.2 and NaVβ1 coassemble. (F) Mouse cerebral cortex immunostained for KV1.2 (green; Left) and NaVβ1 (red; Center), showing colocalization in the axon initial segment in the merged image (Right).
Fig. 2.
Fig. 2.
Activation kinetics (A, D, G, and J), voltage dependence of activation (B, E, H, and K) (mean ± SEM), and deactivation kinetics (C, F, I, and L) of KV1.1, KV1.3, KV1.6, and KV3.1 expressed alone (black) or with NaVβ1 (red) in Xenopus oocytes (KV1.1, KV1.3, and KV1.6) or mammalian cells (KV3.1) (n ≥ 5). (M) Western blot of coimmunoprecipitation experiment in transfected HEK cells showing that KV7.2 and NaVβ1 coprecipitate. (N) NaVβ1 slows activation of the KV7.2 current in CHO cells at moderate depolarizing potentials (n = 5). (O) Relative instantaneous current of KV7.2 shows a significant difference in the 1-s prepulse potential in the presence of NaVβ1 (n = 9).
Fig. 3.
Fig. 3.
Schematic representation of NaVβ1 (red), myelin P0 protein (blue), and their chimeras (A). Inset, Extracellular domain of NaVβ1 showing the R85C and C121W epilepsy-causing mutations. (B and E) Effect on KV1.2 and KV1.3 activation kinetics by NaVβ1 versus P0 (B and E), chimeras (C and F), and NaVβ1 mutants (D and G) studied in Xenopus oocytes. Current traces are averages of normalized, representative currents of comparable amplitudes and shown are the first 30-ms activating phase of the 200-ms traces.
Fig. 4.
Fig. 4.
Activation kinetics (A and B), voltage dependence of activation (D and E; mean ± SEM), cumulative inactivation (G and H), and deactivation of KV1.1–KV1.3 and the KV1.3–KV1.1 chimeras (J and K), expressed alone (black) or with NaVβ1 (red) in Xenopus oocytes. Schematic showing interaction between NaVβ1 and domains within the channel chimeras (C, F, I, and L). Current traces shown are averages of normalized currents of selective sample currents of comparable amplitudes. Side view (M) and view from the extracellular side of the membrane (N) of the model of the complex of KV1.2 with NaVβ1. The channel monomers are colored in four different shades of blue, NaVβ1 in tan, and residues that are lipid exposed on the S1 and S5 segments and that differ in character to equivalent residues in other KV channel families are displayed as green and orange spheres, respectively.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Catterall WA, Goldin AL, Waxman SG. International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev. 2005;57(4):397–409. - PubMed
    1. Luján R. Organisation of potassium channels on the neuronal surface. J Chem Neuroanat. 2010;40(1):1–20. - PubMed
    1. Vacher H, Mohapatra DP, Trimmer JS. Localization and targeting of voltage-dependent ion channels in mammalian central neurons. Physiol Rev. 2008;88(4):1407–1447. - PMC - PubMed
    1. Brackenbury WJ, Isom LL. Na channel β subunits: Overachievers of the ion channel family. Front Pharmacol. 2011;2:53. - PMC - PubMed
    1. Oyama F, et al. Sodium channel beta4 subunit: Down-regulation and possible involvement in neuritic degeneration in Huntington’s disease transgenic mice. J Neurochem. 2006;98(2):518–529. - PubMed

Publication types

Substances