KCNN2

Calcium activates potassium channels in response to changes in intracellular calcium concentration and couples calcium metabolism with potassium flux and membrane excitability. According to its electrophysiological characteristics, there are three types of large conductance (BK), medium conductance (MK) and small conductance (SK). Among them, the channel SK2, which is encoded by the KCNN2 gene, belongs to one of the small conductance subtypes.

Small conductance Ca²⁺ activated K⁺ channels (SK) channels are independent of voltage and are only activated by intracellular Ca²⁺. Functional SK channels are heteromeric complexes with constitutively bound calmodulin, and channel opening occurs in response to the binding of Ca²⁺ to calmodulin. They are selectively blocked by the melittin apamin. In neurons, SK channels are activated by transient increases in intracellular calcium that occur during the action potential. Their activation hyperpolarizes the membrane, thereby reducing cell excitability for tens of milliseconds after each action potential. Electrophysiological and pharmacological studies have shown that SK channels are responsible for the neutralization and/or long latency components of AHP. They have a strong influence on the excitability of neurons and participate in the regulation of neuronal firing.

Figure 1. Four SK2 proteins, each bound to one CaM protein, form the voltage-independent calcium-activated SK2 channel. (Form Mutagenetix)

KCNN2 Cloning and Expression

By screening the Jurkat T cell cDNA library using RT-PCR based on degenerate primers of the rat and human SK channels, and then searching the EST database, the researchers isolated a cDNA encoding KCNN2, which they called SK2. Sequence analysis predicts that 579 amino acids in the human protein encoded by this gene are 97% identical to the rat sequence, containing multiple phosphorylation sites and no N-glycosylation sites. Northern blot analysis detected a major 2.5 kb transcript, which was most strongly expressed in the liver and brain, and had low expression levels in the kidney and Jurkat (but not peripheral) T cells. A 4.4kb transcript was expressed in the heart and skeletal muscle, and a 1.3kb transcript was expressed in the brain and liver. Functional analysis showed that KCNN2 expresses potassium currents and is sensitive to apamin, Scyllatoxin and tubocurarine, but not to charybdotoxin.

KCNN2 and Disease

Atrial Fibrillation

Atrial fibrillation is a type of arrhythmia. Studies have shown that after atrial fibrillation occurs, ion channels in atrial tissue are remodeled, which significantly shortens the duration of action potentials, which makes it easier to maintain atrial fibrillation, and then manifests as "electrical remodeling." The functional subunit of the type 2 small conductance calcium-activated potassium channel (SK2) is encoded by the KCNN2 gene, and belongs to one of the members of the calcium-activated potassium channel gene family. It has been reported in the literature that the change of KCNN2 gene expression is closely related to atrial fibrillation. Studies have shown that the expression of KCNN2 gene in the atrium is higher than that of the ventricle, and melittin at a concentration of 100 pM can specifically block its function. Further research shows that short-term stimulation of the pulmonary vein can trigger the increase of KCNN2 gene expression level, promote the transfer of the protein membrane, and increase the current density at the whole cell level, which in turn triggers atrial fibrillation. Therefore, the KCNN2 gene is considered to be an ideal target for the treatment of atrial fibrillation.

References

1. Schumacher, M. A., et al.; Structure of the gating domain of a Ca(2+)-activated K+ channel complexed with Ca(2+)/calmodulin. Nature. 2001, 410: 1120-1124.
2. Szatanik, M., et al.; Behavioral effects of a deletion in Kcnn2, the gene encoding the SK2 subunit of small-conductance Ca(2+)-activated K(+) channels. Neurogenetics. 2008, 9: 237-248.
3. Mitra R, et al.; SK2 potassium channel over-expression in basolateral amygdala reduces anxiety, stress-induced corticosterone and dendritic arborization. Mol. Psychiatry. 2009, 14 (9): 847–55, 827.