KCNA3

Voltage-gated potassium channel, a member of the exciter-related subfamily 3, called Kv1.3, is a protein encoded by the human KCNA3 gene. The outward delayed rectification Kv1.3 current is usually activated at a membrane voltage of 35 mV. These currents appear as c-type inactivation and typical cumulative inactivation. Kv1.3 channels are widely distributed and expressed in tissues such as B, T lymphocytes, macrophages, olfactory bulbs, and epithelium. Studies have found that Kv1.3 channels are involved in the activation and proliferation of B lymphocytes and T lymphocytes, and are present in immune synapses during antigen presentation. Therefore, they are related to autoimmune diseases. Although Kv1.3 is mainly detected on the plasma membrane, Kv1.3 is also present in the inner mitochondrial membrane (IMM) of lymphocytes and is involved in cell apoptosis. Kv1.3 is also involved in the insulin signaling pathway, which is related to insulin sensitivity and obesity.

Figure 1. Diagrammatic representation of the proposed mechanism for Kv1.3-induced respiration and proliferation(Styles FL, et al.; 2021).

KCNA3 Cloning and Expression

Lymphocytes express three different types of voltage-gated potassium channels according to their function, activation state and developmental timing. These are called n, n'and l. n potassium channels play an important role in the proliferation and activation of human T cells. These three channels are encoded by the mouse MK1, MK2 and MK3 genes; the potassium channel is encoded by the MK3 gene. Philipson et al. isolated cDNAs encoding three human potassium channels PCN1, PCN2 and PCN3.

Function of KCNA3 Protein

Kv1.3 is a membrane protein that selectively permeates potassium ions and is activated when the cell membrane voltage changes. Activation of this channel provides the transport of potassium ions across the cell membrane along its electrochemical gradient. Studies have shown that KCNA3 can effectively promote nerve cells to repolarize after an action potential that prevents nerve cells from overexciting. The abnormal expression of KCNA3 is related to the pathology of a variety of neurodegenerative diseases. In addition, high levels of KCNA3 were also found in T and B lymphocytes. KCNA3 has been shown to play a very important role in T cell proliferation and activation. The lack of KCNA3 inhibits the proliferation and activation of T cells. Recent studies have shown that KCNA3 blockers can selectively inhibit the effect of effector memory T cells and relieve the symptoms of autoimmune diseases without affecting the protective immune response.

KCNA3 and Disease

There are Kv1.3 type Kv channels in the plasma membrane of human T lymphocytes. The activation of the Kv1.3 channel in the plasma membrane allows potassium ions to flow out of the cell and stabilizes the resting membrane potential. Kv1.3 channels are found in human T and B lymphocytes, macrophages, fibroblasts, platelets, macrophages, osteoclasts, microglia, oligodendrocytes, brain (e.g., olfactory bulb, hippocampus, and brain Cortex), lungs, pancreatic islets, thymus, spleen, lymph nodes and testes. Interestingly, the Kv1.3 channel is also in abnormal T lymphocytes and cancer cells, such as the human leukemia T cell line Jurkat, prostate cancer PC-3 cells and breast cancer MCF-7 cells in the inner mitochondrial membrane (mito Kv1.3) In the expression. Recently published data indicate that Kv1.3 channels are also expressed in the nucleus of cancer cells, such as, breast cancer MCF-7, lung cancer A549 and gastric cancer SNU-484 cells, and human brain tissue. In addition, Kv1.3 channels were found in the cis-Golgi membranes of rat cancerous astrocytoma C6 cells and non-cancerous CTX TNA2 astrocyte cell lines and rat primary astrocytes. And research has found that the activity of Kv1.3 channel plays an important role in cell proliferation and apoptosis. Many chemically unrelated compounds can inhibit channel activity, such as heavy metal cations, small organic compounds, and venom-separated oligopeptides. The most effective specific inhibitors inhibit channel activity at sub-nanomolar concentrations. Clinical studies have found that specific inhibitors that inhibit the Kv1.3 channel may be beneficial in the treatment of autoimmune diseases mediated by T lymphocytes (for example, multiple sclerosis, type I diabetes, rheumatoid arthritis, psoriasis), Chronic renal failure, asthma, obesity, type 2 diabetes, cognitive impairment and certain cancer diseases.

References

1. Grissmer, S., et al.; Expression and chromosomal localization of a lymphocyte K+ channel gene. Proc. Nat. Acad. Sci. 1990, 87: 9411-9415.
2. Rus, H., et al.; The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain. Proc. Nat. Acad. Sci. 2005, 102: 11094-11099.
3. Chen Y.J., et al.; Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke. Annals of Clinical & Translational Neurology. 2018, 5(2):147-161.
4. Yuan X.L., et al.; A Kv1.3 channel-specific blocker alleviates neurological impairment through inhibiting T-cell activation in experimental autoimmune encephalomyelitis. Cns Neuroscience & Therapeutics. 2018, 24(10):967-977.
5. Grimaldi A., et al.; Kv1.3 activity perturbs the homeostatic properties of astrocytes in glioma. Sci Rep. 2018, 8(1):7654.
6. Bozic I., et al.; Voltage gated potassium channel Kv1.3 is upregulated on activated astrocytes in experimental autoimmune encephalomyelitis. Neurochemical Research. 2018, 43(5):1020-1034.
7. Styles FL, et al.; Kv1.3 voltage-gated potassium channels link cellular respiration to proliferation through a non-conducting mechanism. Cell Death Dis. 2021, 12(4):372.