Fortunately, Kv1.3 is characterized by a very selective and potent pharmacology that has been demonstrated to ameliorate autoimmune and metabolic symptoms in disease-animal models without major side effects. Moreover, Kv1.3 blockers are showing positive results in preclinical trials. Considering this evidence, the implication of Kv1.3 in a wide repertoire of human pathologies indicates this channel is an important therapeutic target.

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The voltage‐dependent potassium (Kv) channel Kv1.3 regulates leukocyte proliferation, activation, and apoptosis, and altered expression of this channel is linked to autoimmune diseases. Thus, the fine‐tuning of Kv1.3 function is crucial for the immune system response. The Kv1.3 accessory protein, potassium voltage‐gated channel subfamily E (KCNE) subunit 4, acts as a dominant negative regulatory subunit to both enhance inactivation and induce intracellular retention of Kv1.3. Mutations in KCNE4 also cause immune system dysfunction. Although the formation of Kv1.3‐KCNE4 complexes has profound consequences for leukocyte physiology, the molecular determinants involved in the Kv1.3‐KCNE4 association are unknown. We now show that KCNE4 associates with Kv1.3 via a tetraleucine motif situated within the carboxy‐terminal domain of this accessory protein. This motif would function as an interaction platform, in which Kv1.3 and Ca2+/calmodulin compete for the KCNE4 interaction. Finally, we propose a structural model of the Kv1.3‐KCNE4 complex. Our experimental data and the in silico structure suggest that the KCNE4 interaction hides a forward‐trafficking motif within Kv1.3 in addition to adding a strong endoplasmic reticulum retention signature to the Kv1.3‐KCNE4 complex. Thus, the oligomeric composition of the Kv1.3 channelosome fine‐tunes the precise balance between anterograde and intracellular retention elements that control the cell surface expression of Kv1.3 and immune system physiology.—Sole, L., Roig, S. R., Sastre, D., Vallejo‐Gracia, A., Serrano‐Albarrás, A., Ferrer‐Montiel, A., Fernández‐Ballester, G., Tamkun, M. M., Felipe, A. The calmodulin‐binding tetraleucine motif of KCNE4 is responsible for association with Kv1.3. FASEB J. 33, 8263–8279 (2019). http://www.fasebj.org

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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