KCNN3

SK3 (small conductance calcium-activated potassium channel 3), also known as KCa2.3, is a channel protein, which is encoded by the Ca-activated K⁺ channel protein gene 3 (KCNN3) gene in humans.

Figure 1. The Structure of KCNN3. (Christiane K. Bauer, et al.; 2019)

SK3 is a small-conductivity calcium-activated potassium channel responsible for part of the calcium-dependent hyperpolarized current (I AHP). It belongs to the family of so-called small conductance potassium channels. The family consists of three members-SK1, SK2 and SK3 (encoded by KCNN1, 2 and 3 genes respectively), which share 60-70% sequence identity. The study found that the above three types of genes were located at 19p13.1, 5q, and 1q21.3 respectively. Among these three chromosomes, except chromosome 19, the other two chromosome genome scans have found susceptibility genes for schizophrenia, and KCNN3 is a gene that has been studied more related to schizophrenia. Functional SKCa channel protein is composed of The three subunits of SKCa1~3 are composed of homoploid and aneuploid. Each subunit contains 6 transmembrane double helix structures (S1S6) and intracellular amino terminal and carboxyl terminal.

KCNN3 Function

The protein encoded by the KCNN3 gene has ion channel activity, and it combines with calmodulin to form a component of cell membrane tissue. Existing studies have shown that KCNN3 encodes protein and ion transport (including potassium ions), synaptic transmission, nerve cell development and growth, calcium-activated potassium channel activity, constitutes a voltage-gated potassium channel complex and small current calcium-activated potassium channel activity And other functions.

KCNN3 Pathophysiology

Ca²⁺ signal cascade amplification plays an important role in the functional activation of different tissues. Ca²⁺ activated K⁺ channels (KCa) affect a series of intracellular effects mediated by Ca²⁺ by regulating excitatory and non-exciting cell membrane action potentials. KCa channels are classified into large, medium and small according to their single channel conductance. Small conductance K channel (SKCa) has a conductance of 4 to 14 pS, which is a voltage-dependent K channel. The concentration of Ca²⁺ in its cytoplasm usually fluctuates between 200 and 500 nM. In the central nervous system, these channels regulate neuronal firing patterns by producing slow post-membrane hyperpolarization.

KCNN3 and Schizophrenia

Human SKCa3 is also called KCNN3 or SK3. It has been reported that human chromosome 1q21 contains an important susceptibility site for certain familial schizophrenia. The amino terminus of SKCa3 channel protein contains a highly polymorphic polyglutamic acid repeat (CAG)n. Related studies in different populations have found that long polyglutamate repeats are significantly overexpressed in patients with schizophrenia, and it is found to be highly correlated with negative symptoms of schizophrenia. However, some family studies reported that short polyglutamate repeats were overexpressed in patients with schizophrenia. On the contrary, many family studies failed to confirm that the length of SKCa channel protein gene (CAG) n was related to schizophrenia. A genetic study of the family genetics of patients with schizophrenia found a rare 4 base deletion in the SKCa gene. This frameshift mutation caused a truncated SKCa polymorphism. △SKCa3 terminates prematurely at the 286th amino acid residue, and the truncated protein spans the entire amino terminus, lacking a hydrophobic core and carboxy terminus. These mutant proteins alone or in combination with the protein products of normal alleles affect their normal channel function. In view of the tetrameric nature of these channel proteins, it is possible for the mutant protein to gather together in all normal SKCa subunits encoded by the three sites in this gene family to inhibit all endogenous SKCa currents in a dominant negative manner. This inhibitory effect was confirmed by truncating the apical amino-terminal SKCa protein similar to the amino-terminal SKCa2 fragment.

Folding KCNN3 Gene Increases the Risk of Atrial Fibrillation

An international research team led by German scientists announced that they have discovered a gene that greatly increases the risk of atrial fibrillation (AF). The researchers compared and analyzed the genomes of 1,335 patients with so-called isolated atrial fibrillation without other heart diseases and more than 10,000 healthy people, and finally discovered the KCNN3 gene, which significantly increases the risk of atrial fibrillation. Researchers discovered that this gene is involved in the synthesis of a potassium channel that affects cardiac pacing.

References

1. Chandy KG, et al.; Isolation of a novel potassium channel gene hSKCa3 containing a polymorphic CAG repeat: a candidate for schizophrenia and bipolar disorder? Mol. Psychiatry. 1998, 3 (1): 32–7.
2. Wei AD, et al.; International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated potassium channels. Pharmacol. Rev. 2005, 57 (4): 463–72.
3. Chen MX, et al.; Small and intermediate conductance Ca(2+)-activated K+ channels confer distinctive patterns of distribution in human tissues and differential cellular localisation in the colon and corpus cavernosum. Naunyn Schmiedebergs Arch. Pharmacol. 2004, 369 (6): 602–15.
4.  Austin, C. P., et al.; Mapping of hKCa3 to chromosome 1q21 and investigation of linkage of CAG repeat polymorphism to schizophrenia. Molec. Psychiat. 1999, 4: 261-266.
5. Christiane K. Bauer, et al.; Gain-of-Function Mutations in KCNN3 Encoding the Small-Conductance Ca2+-Activated K+ Channel SK3 Cause Zimmermann-Laband Syndrome. The American Journal of Human Genetics. 2019. 104(6).