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2017-02-10

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cc-by (c) Martínez Mármol, Ramón et al., 2017
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/120567

Ubiquitination mediates Kv1.3 endocytosis as a mechanism for protein Kinase C-dependent modulation

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https://doi.org/10.1038/srep42395

Abstract

The voltage-dependent potassium channel Kv1.3 plays essential physiological functions in the immune system. Kv1.3, regulating the membrane potential, facilitates downstream Ca2+ -dependent pathways and becomes concentrated in specific membrane microdomains that serve as signaling platforms. Increased and/or delocalized expression of the channel is observed at the onset of several autoimmune diseases. In this work, we show that adenosine (ADO), which is a potent endogenous modulator, stimulates PKC, thereby causing immunosuppression. PKC activation triggers down-regulation of Kv1.3 by inducing a clathrin-mediated endocytic event that targets the channel to lysosomal-degradative compartments. Therefore, the abundance of Kv1.3 at the cell surface decreases, which is clearly compatible with an effective anti-inflammatory response. This mechanism requires ubiquitination of Kv1.3, catalyzed by the E3 ubiquitin-ligase Nedd4-2. Postsynaptic density protein 95 (PSD-95), a member of the MAGUK family, recruits Kv1.3 into lipid-raft microdomains and protects the channel against ubiquitination and endocytosis. Therefore, the Kv1.3/PSD-95 association fine-tunes the anti-inflammatory response in leukocytes. Because Kv1.3 is a promising multi-therapeutic target against human pathologies, our results have physiological relevance. In addition, this work elucidates the ADO-dependent PKC-mediated molecular mechanism that triggers immunomodulation by targeting Kv1.3 in leukocytes.

Subject

Sistema nerviós, Ubiqüitina

Subject (English)

Nervous system, Ubiquitin

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Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut de Biomedicina (IBUB))

Citation

MARTÍNEZ MÁRMOL, Ramón, et al. Ubiquitination mediates Kv1.3 endocytosis as a mechanism for protein Kinase C-dependent modulation. Scientific Reports. 2017. Vol. 7, num. 42395. ISSN 2045-2322. [consulted: 9 of August of 2026]. Available at: https://hdl.handle.net/2445/120567

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