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dc.contributor.author | Martínez Mármol, Ramón |
---|---|
dc.contributor.author | Styrczewska, Katarzyna |
dc.contributor.author | Pérez Verdaguer, Mireia |
dc.contributor.author | Vallejo Gracia, Albert |
dc.contributor.author | Comes i Beltrán, Núria |
dc.contributor.author | Sorkin, Alexander |
dc.contributor.author | Felipe Campo, Antonio |
dc.date | 2018-03-08T15:02:14Z |
dc.date | 2018-03-08T15:02:14Z |
dc.date | 2017-02-10 |
dc.date | 2018-03-08T15:02:14Z |
dc.identifier | 2045-2322 |
dc.identifier | 670571 |
dc.identifier | 28186199 |
dc.identifier.uri | http://hdl.handle.net/2445/120567 |
dc.description | 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. |
dc.format | application/pdf |
dc.language | eng |
dc.publisher | Nature Publishing Group |
dc.relation | Reproducció del document publicat a: https://doi.org/10.1038/srep42395 |
dc.relation | Scientific Reports, 2017, vol. 7, num. 42395 |
dc.relation | https://doi.org/10.1038/srep42395 |
dc.rights | cc-by (c) Martínez Mármol, Ramón et al., 2017 |
dc.rights | http://creativecommons.org/licenses/by/3.0/es |
dc.rights | info:eu-repo/semantics/openAccess |
dc.subject | Sistema nerviós |
dc.subject | Ubiqüitina |
dc.subject | Nervous system |
dc.subject | Ubiquitin |
dc.title | Ubiquitination mediates Kv1.3 endocytosis as a mechanism for protein Kinase C-dependent modulation |
dc.type | info:eu-repo/semantics/article |
dc.type | info:eu-repo/semantics/publishedVersion |