Modulation of the voltage-gated potassium channel Kv1.5 by the SGK1 protein kinase involves inhibition of channel ubiquitination
Abstract
The serum and glucocorticoid inducible kinase SGK1 is involved in dexamethasone-induced inhibition of insulin secretion by increasing voltage-gated potassium channel (Kv) activity. SGK1 upregulates the Kv1.5 channel but the precise mechanism underlying the SGK1 dependent regulation of Kv1.5 has not been defined yet. The present study explored the signal transduction processes involved. Expression studies in Xenopus oocytes revealed that SGK1 promotes channel activity by interfering with the Nedd4-2 ubiquitination pathway, irrespective of the presence of putative SGK1 phosphorylation sites on Kv1.5. Expression of the ubiquitin ligase Nedd4-2 declined Kv1.5 currents by ubiquitinating and thereby reducing Kv1.5 plasma membrane expression. Increasing concentrations of SGK1 gradually compensated the inhibiting effect of Nedd4-2 on Kv1.5. Enhanced Kv1.5 surface abundance by SGK1 reflects decreased channel internalization as indicated by Brefeldin A experiments. In conclusion, Kv1.5 upregulation by SGK1 involves inhibition of channel ubiquitination by Nedd4-2 that leads to Kv1.5 stabilization in the plasma membrane. Our results suggest that the kinase might participate in the regulation of insulin secretion in part by controlling Kv1.5 surface abundance.
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SGK1 increases the protein abundance and/or activity of a variety of ion channels, carriers, and the Na+/K+-ATPase.
“SGK1 increases the protein abundance and/or activity of a variety of ion channels (e.g.SCN5A, ENaC, ASIC1, TRPV5,6, ROMK, Kv1.1-5, KCNE1/KCNQ1, KCNQ2-5, GluR6, VSOAC, ClC2, CFTR), carriers (e.g.NHE3, NKCC2, NCC, NaPiIIb, SMIT, GLUT1,4, SGLT1, NaDC, EAAT1-5, SN1, ASCT2, 4F2/LAT, PepT2, CreaT), and the Na + /K + -ATPase”
From Significance of SGK1 in the regulation of neuronal function (2010) · cites this paper as Boehmer et al. 2008a,b
Cites
(Patho)physiological Significance of the Serum- and Glucocorticoid-Inducible Kinase Isoforms
Lang, F., Böhmer, C., Palmada, M., Seebohm, G., Strutz-Seebohm, N., & Vallon, V. (2006) · Physiological Reviews · doi:10.1152/physrev.00050.2005 · Cited by 689 · see citing works
Self-citationLambillotte, C., Gilon, P., & Henquin, J. C. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119175 · Cited by 419 · see citing works
Frödin, M., Antal, T. L., Dümmler, B. A., Jensen, C. J., Deak, M., Gammeltoft, S., & Biondi, R. M. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf551 · Cited by 275 · see citing works
Effect of adrenal steroids on insulin release from cultured rat islets of Langerhans
Pierluissi, J., Navas, F. O., & Ashcroft, S. J. H. (1986) · Diabetologia · doi:10.1007/bf00456122 · Cited by 66 · see citing works
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Significance of SGK1 in the regulation of neuronal function
Lang, F., Strutz-Seebohm, N., Seebohm, G., & Lang, U. E. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.190926 · Cited by 170 · see citing works
Self-citation
- Authors
- Boehmer, C., Laufer, J., Jeyaraj, S., Klaus, F., Lindner, R., Lang, F., & Palmada, M.
- Affiliations
- University of Duisburg-Essen (DE)
- University of Tübingen (DE)
- Venue
- Cellular Physiology and Biochemistry
- Publisher
- S. Karger AG
- Published
- 2008
- Volume
- 22
- Issue
- 5-6
- Pages
- 591-600
- ISSN
- 1015-8987 (ISSN-L)
- 1421-9778
- OpenAlex
- W2084240121
- Cited by
- 82
- References
- 4
- Citations by year
- 2024: 1 · 2023: 1 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 3 · 2015: 3 · 2014: 2 · 2013: 6 · 2012: 8
- FWCI
- 6.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cellular Physiology and Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- SGK1, Kv1.5, voltage-gated potassium channels, Nedd4-2, ubiquitination, insulin secretion, dexamethasone, channel surface expression, channel internalization, plasma membrane trafficking, signal transduction
- MeSH terms
- Nedd4 Ubiquitin Protein Ligases, Serum-Glucocorticoid Regulated Kinases, Animals, Cell Membrane, Dexamethasone, Insulin, Kinetics, Xenopus, Ion Channel Gating, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Xenopus Proteins, Ubiquitin-Protein Ligases, Kv1.5 Potassium Channel, Ubiquitination, Endosomal Sorting Complexes Required for Transport
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