Ubiquitin ligase Nedd4-2 modulates Kv1.3 current amplitude and ion channel protein targeting
Open accessAbstract
Voltage-dependent potassium channels (Kv) go beyond the stabilization of the resting potential and regulate biochemical pathways, regulate intracellular signaling, and detect energy homeostasis. Because targeted deletion and pharmacological block of the Kv1.3 channel protein produce marked changes in metabolism, resistance to diet-induced obesity, and changes in olfactory structure and function, this investigation explored Nedd4-2-mediated ubiquitination and degradation to regulate Kv1.3 channel density. Heterologous coexpression of Nedd4-2 ligase and Kv1.3 in HEK 293 cells reduced Kv1.3 current density without modulation of kinetic properties as measured by patch-clamp electrophysiology. Modulation of current density was dependent on ligase activity and was lost through point mutation of cysteine 938 in the catalytic site of the ligase (Nedd4-2CS). Incorporation of adaptor protein Grb10 relieved Nedd4-2-induced current suppression as did application of the proteasome inhibitor Mg-132. SDS-PAGE and immunoprecipitation strategies demonstrated a channel/adaptor/ligase signalplex. Pixel immunodensity was reduced for Kv1.3 in the presence of Nedd4-2, which was eliminated upon additional incorporation of Grb10. We confirmed Nedd4-2/Grb10 coimmunoprecipitation and observed an increased immunodensity for Nedd4-2 in the presence of Kv1.3 plus Grb10, regardless of whether the catalytic site was active. Kv1.3/Nedd4-2 were reciprocally coimmunoprecipated, whereby mutation of the COOH-terminal, SH3-recognition (493-498), or ubiquitination sites on Kv1.3 (lysines 467, 476, 498) retained coimmunoprecipitation, while the latter prevented the reduction in channel density. A model is presented for which an atypical interaction outside the canonical PY motif may permit channel/ligase interaction to lead to protein degradation and reduced current density, which can involve Nedd4-2/Grb10 interactions to disrupt Kv1.3 loss of current density.
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SGK1 mitigates Nedd4-2-mediated internalization of Kv7.2/3 channels, thereby regulating M-current and neuronal excitability, through phosphorylation of Nedd4-2.
“SGK1 mitigates the Nedd4–2-mediated internalization of Kv7.2/3 channels, thereby regulating M-current and neuronal excitability, through the phosphorylation of Nedd4–2”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Velez et al., 2016
The Abstract reports that Nedd4-2 reduces Kv1.3 current density and that Grb10 relieves this suppression. Our copy does not address SGK1 phosphorylation of Nedd4-2, Kv7.2/3 internalization, or M-current; searches for SGK1 and Kv7.2/3 found no passage supporting that mechanism. (LLM, conf=0.75)
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Research works printed but not linked: 2
- Jurman ME, Boland LM, Liu Y, Yellen G. Visual identification of individ- ual transfected cells for electrophysiology using antibody-coated beads. Biotechniques 17: 876 -881, 1994. NEDD4-2 MODULATION OF KV1.3 CHANNEL J Neurophysiol • doi:10.1152/jn.00874.2015 • www.jn.org Downloaded from journals.physiology.org/journal/jn (192.126.247.064) on August 19, 2023.
- Korn SJ, Trapani JG. Potassium channels. IEEE Trans Nanobioscience 4: 21-33, 2005.
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Ubiquitination mediates Kv1.3 endocytosis as a mechanism for protein kinase C-dependent modulation
Martínez-Mármol, R., Styrczewska, K., Pérez-Verdaguer, M., Vallejo-Gracia, A., Comes, N., Sorkin, A., & Felipe, A. (2017) · Scientific Reports · doi:10.1038/srep42395 · Cited by 27 · see citing works
Mitochondrial Ultrastructure and Glucose Signaling Pathways Attributed to the Kv1.3 Ion Channel
Kovach, C. P., Al Koborssy, D., Huang, Z., Chelette, B. M., Fadool, J. M., & Fadool, D. A. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00178 · Cited by 20 · see citing works
Self-citationSerum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain
Howard, P. G., Zou, P., Zhang, Y., Huang, F., Tesic, V., Wu, C. Y.-C., & Lee, R. H.-C. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114973 · Cited by 13 · see citing works
- Authors
- Vélez, P., Schwartz, A. B., Iyer, S. R., Warrington, A., & Fadool, D. A.
- Affiliations
- Florida State University (US)
- Corresponding author
- Fadool, Debra Ann
- Venue
- Journal of Neurophysiology
- Publisher
- American Physiological Society
- Published
- 2016-08-01
- Volume
- 116
- Issue
- 2
- Pages
- 671-685
- ISSN
- 0022-3077 (ISSN-L)
- 1522-1598
- PMC
- PMC4982906
- OpenAlex
- W2345850421
- Cited by
- 16
- References
- 0
- Citations by year
- 2025: 2 · 2024: 1 · 2022: 2 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 4 · 2016: 2
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurophysiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (NIDCD) (R01DC003387, R01DC013080)
- University Legacy Fellowship (Florida State University)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- Nedd4-2, Kv1.3 potassium channel, voltage-gated potassium channels, ubiquitination, protein degradation, Grb10, adaptor proteins, channel density, current amplitude, SH3 domain, proteasome, ubiquitin ligase
- MeSH terms
- Nedd4 Ubiquitin Protein Ligases, Animals, Antibodies, Cell Line, Transformed, Cysteine, Electric Stimulation, Gene Expression Regulation, Humans, Leupeptins, Lysine, Membrane Potentials, Models, Biological, Mutation, Down-Regulation, Cysteine Proteinase Inhibitors, Patch-Clamp Techniques, RNA-Binding Protein FUS, Ubiquitin-Protein Ligases, GRB10 Adaptor Protein, Kv1.3 Potassium Channel, Ubiquitination, Endosomal Sorting Complexes Required for Transport, HEK293 Cells
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