Kv1.3 Potassium Channels: Promising Therapeutic Targets in Hematological Malignancies

Voltage-gated potassium channels (Kv) are selectively permeable for potassium ions and are activated by change of the cell membrane voltage [1]. They are grouped into 12 subfamilies (Kv1-Kv12) with the Kv1 subfamily named Shaker type. Kv channels consist of a homotetramer with four α-subunits and a central ion pore. Each α-subunit is composed of six transmembrane domains S1-S6, S4 serving as voltage-gate, S5 and S6 forming the p-loop as selective potassium ion filter. The α-subunits are associated with regulatory subunits such as Kvß, which control channel expression, gating, and potassium current, with integrins [2] and with adapter proteins and protein tyrosine kinase p56lck, which are involved in signal transduction [3]. Initially studied in excitable cells like neurons, expression of Kv channels was detected in different cell types including hematopoietic cells, and Kv channels of the Kv1.3 type were firstly described in human T lymphocytes in 1984 [4,5]. Kv1.3 channels of the plasma membrane prevent accidental depolarization of the T-cell, thereby regulating its resting membrane potential. Upon T-cell receptor engagement, Kv1.3 channels are recruited into the immunological synapse [6] and via potassium efflux prevent continuous depolarization generated by calcium influx through calcium release-activated calcium (CRAC) channels. The permissive hyperpolarization is crucial for sustained calcium influx to allow effective T-cell activation [7]. Elegant studies have shown that Kv1.3 channels are also expressed in the mitochondrial membrane (mitoKv1.3), where they function as mediators of the intrinsic apoptosis pathway [8]. Upon an initial apoptotic stimulus, the pro-apoptotic Bcl-2 family member Bax, which is located in the outer mitochondrial membrane, translocates to the mitoKv1.3 and blocks its central channel pore at Lysin128. Inhibition of mitoKv1.3 channels results in mitochondrial hyperpolarization, enhanced production of reactive oxygen species (ROS) and the release of cytochrome C (CytC), which feeds into the activation of Caspase-9 and Caspase-3 [9]. In addition, Abstract