KCNA4

Potassium voltage-gated channel subfamily A member 4, also known as Kv1.4, is a protein encoded by the KCNA4 gene in humans. The protein contains six transmembrane domains with a vibrator-like repeat in the fourth segment. It belongs to the type A potassium current class, and its members may play an important role in regulating the rapid repolarization phase of cardiac action potentials, which may affect the duration of cardiac action potentials. The coding region of this gene is intronless, and this gene is clustered with the genes KCNA3 and KCNA10 on human chromosome 1.

KCNA4 Cloning and Expression

The rat genome encodes a family of potassium channels (K channel) (RCK) homologous to the Shaker channel of Drosophila. The researchers only found that one member of the rat K channel family, RCK4, expresses type A, that is, the rapidly inactivated K channel. Subsequently, the researchers provided the cDNA sequence corresponding to the fetal skeletal muscle potassium channel associated with RCK4. The predicted 653 amino acid PCN2 protein has 55% sequence identity with PCN1. Afterwards, a full-length human cDNA with 97% identity to RCK4 was cloned and named HK1. HK1 mRNA is expressed in the heart, especially in the atria and ventricles. Therefore, they concluded that the K channel formed by the protein may play an important role in regulating the rapid repolarization phase of cardiac action potentials, which may affect the duration of cardiac action potentials.

Figure 1. mRNA expression levels of panel kcna4 (Kv1.4). (Wonjun Noh, et al.; 2019).

By performing RT-PCR on human tissue panels, the scientists observed that KCNA4 is highly expressed in the brain, but low to moderately expressed in the testes, lungs, kidneys, colon, and heart. In addition, KCNA4 was detected in the brain, lens and retinal tissues of adult female mice.

KCNA4 Location

In 1992, researchers mapped the KCNA4 gene to chromosome 11p14-p13. Subsequently, through PCR research on somatic cell hybrids and pulsed field gel electrophoresis (PFGE), KCNA4 was located on 11p14. Somatic cell hybridization analysis showed that the gene is located in the WAGR region. PFGE analysis and comparison with the perfect PFGE map of the region mapped the gene to 11p14.1. By observing the deletion of the WAGR region, it is found that the hemizygous deletion of HK1 has almost no phenotypic effect, which may be because the requirements for controlling the expression level of this gene are not so strict. The HK1 gene is in the wrong position and may be a candidate gene for long QT syndrome. In 1993, scientists used a combination of human-mouse somatic hybridization and isotope in situ hybridization to map the potassium channel gene to 11q13.4-q14.1, which they labeled KCNA4.

KCNA4 Gene Function

KCNA4 plays a functional role mainly through the composed potassium channels, participates in the regulation of the voltage-dependent potassium ion permeability of the excitable membrane, and then participates in the normal physiological processes of the body. Existing studies have shown that the homotetramer of KCNA4 has the function of a delayed rectifier potassium channel, which opens in response to membrane depolarization and then closes through a slow spontaneous channel. The heteromultimer assembled by KCNA1 and KCNA4 showed the characteristic of rapid inactivation. Functional studies have shown that KCNA4 may be involved in the rapid repolarization phase of cardiac action potentials, thereby affecting the duration of cardiac action potentials. In addition, KCNA4 also participates in the regulation of neuropathic pain by controlling the overexcitation of primary sensory neurons. Further research found that KCNA4 is also related to the pathological process of many diseases, including neurological disorders such as epilepsy, depression, autoimmune encephalomyelitis, and congenital cataracts and mental retardation. A recent study also showed that the serum DNA methylation gene of KCNA4 is also involved in the progression of gastric cancer, providing a new potential biomarker for the diagnosis of gastric cancer. In addition, due to its unique properties, KCNA4 can also be used as a promising therapeutic target for various diseases such as epilepsy and depression.

References

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4. Sato T., et al.; Type 2 diabetes induces subendocardium-predominant reduction in transient outward K+ current with downregulation of Kv4.2 and KChIP2. American Journal of Physiology Heart & Circulatory Physiology. 2014, 306(7):1054-65.
5. Carrasquillo Y., et al.; A-type K+ channels encoded by Kv4.2, Kv4.3 and Kv1.4 differentially regulate intrinsic excitability of cortical pyramidal neurons. Journal of Physiology. 2012, 590(16):3877-3890.
6. Gessler, M., et al.; The potassium channel gene HK1 maps to human chromosome 11p14.1, close to the FSHB gene. Hum. Genet. 1992, 90: 319-321.
7. Grandy, D., et al.; A human voltage-gated potassium channel gene, HuKII, maps to chromosome 11p14-p13. Am. J. Hum. Genet. 1992, 51: A396 only.
8. Philipson, L. H., et al.; Sequence of a human fetal skeletal muscle potassium channel cDNA related to RCK4. Nucleic Acids Res. 1990, 18: 7160 only.
9. Tamkun, M. M., et al.; Molecular cloning and characterization of two voltage-gated K+ channel cDNAs from human ventricle. FASEB J. 1991, 5: 331-337.
10. Wonjun Noh, et al.; Transient Potassium Channels:Therapeutic Targets for Brain Disorders. Frontiers in Cellular Neuroscience. 2019, 13:265.