KCNA7

Potassium channels represent the most complex type of voltage-gated ion channel in terms of function and structure. Their different functions include regulation of neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Potassium voltage-gated channel subfamily member 7 is a protein encoded by the KCNA7 gene in humans. The protein encoded by this gene is a voltage-gated potassium channel subunit. The predicted product has 91% amino acid identity with the mouse voltage-gated potassium channel protein Kv1.7 (Kcna7), which plays an important role in the repolarization of the cell membrane. Based on the high similarity, the human gene was classified as an orthologous gene of mouse Kcna7 and named Kv1.7 (KCNA7).

KCNA7 Cloning and Expression

Kalman et al. reported the isolation of mouse voltage-gated shaker-related potassium channel gene Kv1.7 (Kcna7). The Kv1.7 channel of mice is voltage-dependent and exhibits cumulative inactivation. Northern blot analysis showed that there are approximately 3kb transcripts in mouse heart and skeletal muscle. Further research found that the protein encoded by the human KCNA7 gene contains 456 amino acid residues, including cytoplasmic N- and c-terminals, a central core domain composed of 6 transmembrane fragments, and a unique pore ring. Northern expression analysis showed that this gene is preferentially expressed in skeletal muscle, heart and kidney. However, its expression level is lower in other tissues, including the liver.

Figure 1. Schematic presentation of a side view KV1 channel.(Rocio K. Finol-Urdaneta, et al.; 2020)

Using fluorescence in situ hybridization, the gene was mapped to the chromosome 19q13.4. The genome sequence was identified from this region in the database, and the KCNA7 gene structure was determined. Computational analysis of the genome sequence revealed the location of the putative promoter and possible muscle-specific regulatory regions.

KCNA7 and Disease

KCNA7 acts as a voltage-gated potassium channel subunit through the channel function and participates in the regulation of the potassium ion permeability of the excitable membrane according to its electrochemical gradient. Studies have found that Kv1.7 mRNA is expressed in the mouse heart and is involved in the function of the heart. The Kv1.7 homotetramer shares many characteristics with the rapidly inactivated transient outward (I to) current in the Purkinje fibers of the heart, but is different from the I to current in the atrial and ventricular myocytes. Kv1.7 and Purkinje I to currents are activated at negative potentials (-30 to -20 mV) and are rapidly inactivated, showing cumulative inactivation. In contrast, the I to current (product of the Kv4.3 gene) in atrial muscle and ventricular muscle does not show cumulative inactivation. These studies indicate that at least part of Purkinje fiber Ito may be encoded by the Kv1.7 gene, although more extensive biophysical and pharmacological studies are needed to confirm this connection, and the presence of Kv1.7 mRNA and/or protein It has not been confirmed in these fibers. The abundant expression of Kv1.7 mRNA in the mouse heart indicates that this channel may also exist in the ventricle and/or atrial muscle, where it may aggregate with other Kv1 family channels to form heterotetramers.

Recent studies have shown that Kv channels play an important role in regulating pancreatic islet cell function, especially in the membrane potential repolarization after each action potential during the glucose-induced burst phase associated with insulin secretion. Despite these interesting findings, the gene encoding the Kv gene in β cells has not yet been identified. Researchers have demonstrated the presence of Kv1.7 mRNA in β cells. Unlike the non-inactivated Kv channel in pancreatic β cells, the Kv1.7 homotetramer exhibits rapid C-type inactivation. Since Kv1.7 mRNA is expressed in pancreatic islets, heteromultimers composed of Kv1.7 and other Kv1 subunits may constitute the natural Kv channel in β cells. This increase in the level of Kv channels excessively hyperpolarizes the β cell membrane, and impairs insulin secretion. The Kv1.7 gene maps to human chromosome 19q13.3. This region is thought to contain a diabetes susceptibility gene, which also suggests that Kv1.7 may contribute to the pathogenesis of some human type II diabetes.

References

1. Kalman K, et al.; Genomic organization, chromosomal localization, tissue distribution, and biophysical characterization of a novel mammalian Shaker-related voltage-gated potassium channel, Kv1.7. J Biol Chem. 1998 Mar 6;273(10):5851-7.
2. Bardien-Kruger, S., et al.; Characterisation of the human voltage-gated potassium channel gene, KCNA7, a candidate gene for inherited cardiac disorders, and its exclusion as cause of progressive familial heart block I (PFHBI). Europ. J. Hum. Genet. 2002, 10: 36-43.
3. Chandy, K. G., et al.; A family of three mouse potassium channel genes with intronless coding regions. Science. 1990, 247: 973-975.
4. McPherson, J. D., et al.; Chromosomal localization of 7 potassium channel genes. (Abstract) Cytogenet. Cell Genet. 1991, 58: 1979.
5. Rocio K. Finol-Urdaneta, et al.; Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds. Marine Drugs. 2020, 18(3):173.