1.A.1.2.4
Margatoxin-sensitive voltage-gated K⁺ channel, Kv1.3 (in plasma and mitochondrial membranes of T lymphocytes) (Szabò et al., 2005). K_v1.3 associates with the sequence similar (>80%) K_v1.5 protein in macrophage forming heteromers that like K_v1.3 homomers are r-margatoxin sensitive (Vicente et al., 2006). However, the heteromers have different biophysical and pharmacological properties. The K_v1.3 mitochondrial potassium channel is involved in apoptotic signalling in lymphocytes (Gulbins et al., 2010). Interactions between the C-terminus  of K_v1.5 and K_vβ regulate pyridine nucleotide-dependent changes in channel gating (Tipparaju et al., 2012).  Intracellular trafficking of the K_V1.3 K⁺ channel is regulated by the pro-domain of a matrix metalloprotease (Nguyen et al. 2013).  Direct binding of caveolin regulates K_v1 channels and allows association with lipid rafts (Pérez-Verdaguer et al. 2016). Addtionally, Na_vBeta1 interacts with the voltage sensing domain (VSD) of K_v1.3 through W172 in the transmembrane segment to modify the gating process (Kubota et al. 2017). During insertion of Kv1.3, the extended N-terminus of the second α-helix, S2, inside the ribosomal tunnel is converted into a helix in a transition that depends on the nascent peptide sequence at specific tunnel locations (Tu and Deutsch 2017). The microRNA, mmumiR449a, reduced the mRNA expression levels of transient receptor potential cation channel subfamily A member 1 (TRPA1), and calcium activated potassium channel subunit alpha1 (KCNMA1) and increased the level of transmembrane phosphatase with tension homology (TPTE) in the DRG cells (Lu et al. 2017). This channel is regulation by sterols (Balajthy et al. 2017). Loss of function causes atrial fibrillation, a rhythm disorder characterized by chaotic electrical activity of cardiac atria (Olson et al. 2006). The N-terminus and S1 of Kv1.5 can attract and coassemble with the rest of the channel (i.e. Frag(304-613)) to form a functional channel independently of the S1-S2 linkage (Lamothe et al. 2018). This channel may be present in mitochondria (Parrasia et al. 2019). Kv1.3 plays an essential role in the immune response mediated by leukocytes and is functional at both the plasma membrane and the inner mitochondrial membrane. Plasma membrane Kv1.3 mediates cellular activation and proliferation, whereas mitochondrial Kv1.3 participates in cell survival and apoptosis (Capera et al. 2022). Kv1.3 uses the TIM23 complex to translocate to the inner mitochondrial membrane. This mechanism is unconventional because the channel is a multimembrane spanning protein without a defined N-terminal presequence. Transmembrane domains cooperatively mediate Kv1.3 mitochondrial targeting involving the cytosolic HSP70/HSP90 chaperone complex as a key regulator of the process (Capera et al. 2022).  While the COOH-terminus of KCNE4 physically interacts with the channel, its transmembrane domain shapes the inactivation properties of the functional complex, fine-tuning the Kv1.3-dependent physiological response in leukocytes (Sastre et al. 2024).  Neuroactive steroid analogs and voltage-dependent blockers of Ca_V3.2 currents, B372 and YX23, are effective anti-nociceptives with diminished sedative properties in intact female mice (Volvovitz et al. 2025).