The calmodulin‐binding tetraleucine motif of KCNE4 is responsible for association with Kv1.3

Solé, Laura; Roig, Sara R.; Sastre, Daniel; Vallejo-Gracia, Albert; Serrano-Albarrás, Antonio; Ferrer-Montiel, Antonio; Fernández‐Ballester, Gregorio; Tamkun, Michael M.; Felipe, Antônio

doi:10.1096/fj.201801164rr

Cited by 9 publications

(14 citation statements)

References 56 publications

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“…In addition to trafficking, KCNE4 triggered changes in the main inactivating function of the Kv1.3 currents. Thus, as previously reported [14,19], in addition to the characteristic C-type inactivation ( Figure 2E) the cumulative inactivation of Kv1.3, a characteristic use-dependent inactivation in response to trains of action potentials, was greatly affected by the presence of KCNE4 ( Figure 2F,G).…”

Section: Kcne4 Specifically Modulates the Traffic And Activity Of Kv13supporting

confidence: 86%

“…Kv1.3 and KCNE4 are essential for the leukocyte physiology [5,6,13,14,19]. In this context, KCNE4, interacting with Kv1.3, modulates Kv1.3-associated physiology [19,20].…”

Section: Kcne4 Specifically Modulates the Traffic And Activity Of Kv13mentioning

confidence: 99%

“…This outcome could be the results of two main effects: (i) an important intracellular retention of the complex and (ii) changes in channel electrophysiological characteristics. KCNE2 was used as a negative control because does not interact with Kv1.3 [14,19,20]. In contrast to KCNE2, KCNE4 maintains important intracellular complex retention ( Figure 2C).…”

Section: Kcne4 Specifically Modulates the Traffic And Activity Of Kv13mentioning

confidence: 99%

“…In this context, while the structure of the Kv7-KCNE complexes has been studied for decades [18], the Kv1.3-KCNE4 architecture has rarely been examined. We recently explained that the carboxy-terminal domains of both Kv1.3 and KCNE4 are involved in the Kv1.3-KCNE4 association that controls channel behavior [19,20]. However, whether Kv1.3-KCNE4 stoichiometry greatly influences channel function and in turn affects immune physiology remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

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Functional Consequences of the Variable Stoichiometry of the Kv1.3-KCNE4 Complex

Solé

Sastre

Colomer-Molera

et al. 2020

Cells

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The voltage-gated potassium channel Kv1.3 plays a crucial role during the immune response. The channel forms oligomeric complexes by associating with several modulatory subunits. KCNE4, one of the five members of the KCNE family, binds to Kv1.3, altering channel activity and membrane expression. The association of KCNEs with Kv channels is the subject of numerous studies, and the stoichiometry of such associations has led to an ongoing debate. The number of KCNE4 subunits that can interact and modulate Kv1.3 is unknown. KCNE4 transfers important elements to the Kv1.3 channelosome that negatively regulate channel function, thereby fine-tuning leukocyte physiology. The aim of this study was to determine the stoichiometry of the functional Kv1.3-KCNE4 complex. We demonstrate that as many as four KCNE4 subunits can bind to the same Kv1.3 channel, indicating a variable Kv1.3-KCNE4 stoichiometry. While increasing the number of KCNE4 subunits steadily slowed the activation of the channel and decreased the abundance of Kv1.3 at the cell surface, the presence of a single KCNE4 peptide was sufficient for the cooperative enhancement of the inactivating function of the channel. This variable architecture, which depends on KCNE4 availability, differentially affects Kv1.3 function. Therefore, our data indicate that the physiological remodeling of KCNE4 triggers functional consequences for Kv1.3, thus affecting cell physiology.

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Section: Kcne4 Specifically Modulates the Traffic And Activity Of Kv13supporting

confidence: 86%

“…Kv1.3 and KCNE4 are essential for the leukocyte physiology [5,6,13,14,19]. In this context, KCNE4, interacting with Kv1.3, modulates Kv1.3-associated physiology [19,20].…”

Section: Kcne4 Specifically Modulates the Traffic And Activity Of Kv13mentioning

confidence: 99%

Section: Kcne4 Specifically Modulates the Traffic And Activity Of Kv13mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Functional Consequences of the Variable Stoichiometry of the Kv1.3-KCNE4 Complex

Solé

Sastre

Colomer-Molera

et al. 2020

Cells

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“…Furthermore, we observed that delivery of CaM intracellularly through the patch pipette increased KCa3.1, but not Kv1.3 currents in HNSCC T cells. It has been recently reported that CaM binds to the beta subunit of Kv1.3 channels in transfected HEK-293 cells, however this binding does not alter the function of the Kv1.3 channels (Solé et al, 2019). Our data also indicate that increasing the free Ca 2+ concentration in the pipette did not increase the KCa3.1 activity in HNSCC T cells, thus indicating that CaM deficiency, and not a reduction in Ca 2+ sensitivity due to other mechanisms such as changes in CaM and/or channel phosphorylation, is responsible for low KCa3.1 activity in HNSCC T cells (Fanger et al, 1999).…”

Section: Discussionmentioning

confidence: 95%

A Compartmentalized Reduction in Membrane-Proximal Calmodulin Reduces the Immune Surveillance Capabilities of CD8+ T Cells in Head and Neck Cancer

et al. 2020

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The limited ability of cytotoxic CD8 + T cells to infiltrate solid tumors and function within the tumor microenvironment presents a major roadblock to effective immunotherapy. Ion channels and Ca 2+-dependent signaling events control the activity of T cells and are implicated in the failure of immune surveillance in cancer. Reduced KCa3.1 channel activity mediates the heightened inhibitory effect of adenosine on the chemotaxis of circulating T cells from head and neck squamous cell carcinoma (HNSCC) patients. Herein, we conducted experiments that elucidate the mechanisms of KCa3.1 dysfunction and impaired chemotaxis in HNSCC CD8 + T cells. The Ca 2+ sensor calmodulin (CaM) controls multiple cellular functions including KCa3.1 activation. Our data showed that CaM expression is lower in HNSCC than healthy donor (HD) T cells. This reduction was due to an intrinsic decrease in the genes encoding CaM combined to the failure of HNSCC T cells to upregulate CaM upon activation. Furthermore, the reduction in CaM was confined to the plasma membrane and resulted in decreased CaM-KCa3.1 association and KCa3.1 activity (which was rescued by the delivery of CaM). IFNg production, also Ca 2+-and CaMdependent, was instead not reduced in HNSCC T cells, which maintained intact cytoplasmic CaM and Ca 2+ fluxing ability. Knockdown of CaM in HD T cells decreased KCa3.1 activity, but not IFNg production, and reduced their chemotaxis in the presence of adenosine, thus recapitulating HNSCC T cell dysfunction. Activation of KCa3.1 with 1-EBIO restored the ability of CaM knockdown HD T cells to chemotax in the presence of adenosine. Additionally, 1-EBIO enhanced INFg production. Our data showed a localized downregulation of membrane-proximal CaM that suppressed KCa3.1 activity in HNSCC circulating T cells and limited their ability to infiltrate adenosine-rich tumor-like microenvironments. Furthermore, they indicate that KCa3.1 activators could be used as positive CD8 + T cell modulators in cancers.

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Novel integrated workflow allows production and in-depth quality assessment of multifactorial reprogrammed skeletal muscle cells from human stem cells

Faustino

Brinkmeier

Logotheti

et al. 2022

Cell. Mol. Life Sci.

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Skeletal muscle tissue engineering aims at generating biological substitutes that restore, maintain or improve normal muscle function; however, the quality of cells produced by current protocols remains insufficient. Here, we developed a multifactor-based protocol that combines adenovector (AdV)-mediated MYOD expression, small molecule inhibitor and growth factor treatment, and electrical pulse stimulation (EPS) to efficiently reprogram different types of human-derived multipotent stem cells into physiologically functional skeletal muscle cells (SMCs). The protocol was complemented through a novel in silico workflow that allows for in-depth estimation and potentially optimization of the quality of generated muscle tissue, based on the transcriptomes of transdifferentiated cells. We additionally patch-clamped phenotypic SMCs to associate their bioelectrical characteristics with their transcriptome reprogramming. Overall, we set up a comprehensive and dynamic approach at the nexus of viral vector-based technology, bioinformatics, and electrophysiology that facilitates production of high-quality skeletal muscle cells and can guide iterative cycles to improve myo-differentiation protocols.

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The calmodulin‐binding tetraleucine motif of KCNE4 is responsible for association with Kv1.3

Cited by 9 publications

References 56 publications

Functional Consequences of the Variable Stoichiometry of the Kv1.3-KCNE4 Complex

Functional Consequences of the Variable Stoichiometry of the Kv1.3-KCNE4 Complex

A Compartmentalized Reduction in Membrane-Proximal Calmodulin Reduces the Immune Surveillance Capabilities of CD8+ T Cells in Head and Neck Cancer

Novel integrated workflow allows production and in-depth quality assessment of multifactorial reprogrammed skeletal muscle cells from human stem cells

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