Structural determinants at KCNE4 position 145 govern Kv1.3 channel function

Kv1.3 channels participate in the activation and proliferation of leukocytes. The KCNE4 regulatory subunit associates with the channel and functions as a negative regulator. KCNE4, via its transmembrane and C-terminal domains, interacts with Kv1.3, impairing forward plasma membrane trafficking, decreasing macroscopic currents, and accelerating slow C-type inactivation of the channel. A negatively charged 145D/E polymorphic variant of KCNE4 has been associated with immune system disorders, such as allergic rhinitis and childhood acute lymphoblastic leukemia. In this work, we investigated the functional effects of these KCNE4 variants on Kv1.3 activity. Both variants similarly impaired forward trafficking of the channel. However, we observed a variant-dependent decrease in Kv1.3 currents with minor kinetic effects. In addition, we explored the effects of different residues at this position and analyzed the importance of the central amino acid of the polymorphism within the anionic (D-D/E-E) triplet. We suggest that the size and charge of the central position of the cluster are crucial for controlling Kv1.3 currents.