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Abstract
The study of channel modulation by regulatory subunits has attracted considerable attention. Evidence indicates a pivotal role for accessory proteins in the channelosome. For instance, these regulatory subunits are necessary to recapitulate in vivo ion currents and to further understand the physiological role of ion channels. KCNEs are a family of regulatory subunits that interact with a wide range of channels. We have described for the first time a molecular interaction between KCNE4 and the voltage-dependent potassium channel Kv1.3. The association of KCNE4, which alters the biophysical properties, trafficking and membrane localization of Kv1.3, functions as an endogenous dominant-negative mechanism. Since both proteins are expressed in the immune system, Kv1.3/KCNE4 channels may contribute to the fine-tuning of the immune response. Therefore, our results point to KCNE4 as a novel target for immunomodulation. KCNE4 is not the only KCNE which is expressed in leukocytes. All KCNEs (KCNE1-5) are present, and some members demonstrate modulation during proliferation and cancer. In summary, regulatory KCNE subunits are expressed in the immune system. In addition, several voltage-dependent K+ channels, which could interact with KCNEs, are also detected. Therefore, KCNE subunits may play a yet undiscovered role in the physiology of the immune system.
Acknowledgements
The authors thank to all present and past members of the molecular physiology laboratory. Supported by the Ministerio de Ciencia e Innovación (MICINN), Spain (BFU2008-00431 and CSD2008-00005). L.S. is a fellow from MICINN.
Figures and Tables
Figure 1 Human KCNE expression in healthy and cancer tissues. Affymetrix GeneChips HG-U95A-E (GeneNote, http://bioinfo2.weizmann.ac.il/cgi-bin/genenote/home_page.pl) and HG-U133A (GNF, (http://biogps.gnf.org) normalized as described in GeneCard (http://www.genecards.org). Black columns: healthy tissue (GeneNote); Grey columns: healthy tissues (GNF); White columns: cancer samples (GNF).
Figure 2 KCNE expression in human leukocytic cell lines. Array data from GNF BioGPS (http://biogps.gnf.org) normalized according to Su et al.Citation31 Legend: CD34, bone marrow CD34+ progenitors; CD105, endothelial; X212, B lymphoblasts; CD19, B cells; BDCA4, dendritic cells; CD8, CD8+ Tcells; CD4, CD4+ T-cells; CD56, NK cells; CD33, myeloid; CD14, monocytes.
Figure 3 KCNE expression in different human leukemia and lymphoma cell lines. Array data from GNF BioGPS (http://biogps.gnf.org) normalized according to Su et al.Citation31 Legend: MOLT4, Lymphoblastic Leukemia; K.582, Chronic Myelogenous Leukemia; Daudi, Burkitt’s Lymphoma; HL60, Promyelocytic Leukemia; Raji, Burkitt’s Lymphoma.
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