Kv1.3 K⁺Channel Physiology Assessed by Genetic and Pharmacological Modulation

Abstract

Potassium channels are widespread over all kingdoms and play an important role in the maintenance of cellular ionic homeostasis. Kv1.3 is a voltage-gated potassium channel of the Shaker family with a wide tissue expression and a well-defined pharmacology. In recent decades, experiments mainly based on pharmacological modulation of Kv1.3 have highlighted its crucial contribution to different fundamental processes such as regulation of proliferation, apoptosis and metabolism. These findings link channel function to various pathologies ranging from autoimmune diseases to obesity and cancer. In the present review, we briefly summarize studies employing Kv1.3 knockout animal models to confirm such roles and discuss the findings in comparison to the results obtained by pharmacological modulation of Kv1.3 in various pathophysiological settings. We also underline how these studies contributed to our understanding of channel function in vivo and propose possible future directions.

Characterization of endogenous Kv1.3 channel isoforms in T cells

“…Many studies have explored the presence and function of Kv1.3 channel in the mitochondria of both cancer cells and T cells. A MgTx‐ and PAP‐1‐sensitive K + current contributing to mitochondrial potential, whose inhibition induced apoptosis, has been described in these cells (Szabò et al, 2005, 2008; Varanita et al, 2022). In all cases, a protein of the same molecular weight than canonical Kv1.3 channel was identified.…”

A Meta-Analysis Study to Infer Voltage-Gated K+ Channels Prognostic Value in Different Cancer Types

“…Therefore, we focused our observations on identifying a possible relation between KCNA3 and KCNA5 expression and patients’ clinical features and tumor risk factors, such as age, sex, obesity, and smoking. Some previous evidence suggested that KCNA3 plays a regulatory role in the processes of regulating body weight, fat absorption, and insulin sensitivity [ 70 , 71 , 72 , 73 ]. Although the reported data were controversial, it would be worth investigating these relationships in the context of melanoma, considering that KCNA3 associates with a better prognosis in this tumor type ( Figure 2 F).…”

De novo variants in KCNA3 cause developmental and epileptic encephalopathy

“…4 In addition to neurons, where they are primarily targeted to axons and regulate neurotransmitter release, 5,6 Kv1.3 subunits are also expressed in non-excitable cells such as microglia, 7,8 astrocytes, 9 and oligodendrocytes, 10 as well as in T-lymphocytes and vascular smooth muscle cells, where they contribute to cell proliferation, migration and survival. 11 A role for Kv1.3 has been suggested in cancer proliferation, inflammatory stroke response and autoimmune disorders, including diabetes and multiple sclerosis. [12][13][14][15] Pharmacological compounds targeting Kv1.3 are therefore potential candidates for antiproliferative, immune-modulatory and anti-inflammatory effects.…”

“…KCNA3 encodes pore‐forming Kv1.3 subunits highly expressed in selected subpopulations of central neurons in the olfactory bulb, the auditory brainstem, the cerebellum, and in both pyramidal cells and interneurons of the cerebral cortex 4 . In addition to neurons, where they are primarily targeted to axons and regulate neurotransmitter release, 5,6 Kv1.3 subunits are also expressed in non‐excitable cells such as microglia, 7,8 astrocytes, 9 and oligodendrocytes, 10 as well as in T‐lymphocytes and vascular smooth muscle cells, where they contribute to cell proliferation, migration and survival 11 . A role for Kv1.3 has been suggested in cancer proliferation, inflammatory stroke response and autoimmune disorders, including diabetes and multiple sclerosis 12–15 .…”