K_Ca 2.2 (KCNN2): A physiologically and therapeutically important potassium channel

One group of the K⁺ ion channels, the small-conductance Ca²⁺ -activated potassium channels (K_Ca 2.x, also known as SK channels family), is widely expressed in neurons as well as the heart, endothelial cells, etc. They are named small-conductance Ca²⁺ -activated potassium channels (SK channels) due to their comparatively low single-channel conductance of about ~10 pS. These channels are insensitive to changes in membrane potential and are activated solely by rises in the intracellular Ca²⁺ . According to the phylogenic research done on the K_Ca 2.x channels family, there are three channels' subtypes: K_Ca 2.1, K_Ca 2.2, and K_Ca 2.3, which are encoded by KCNN1, KCNN2, and KCNN3 genes, respectively. The K_Ca 2.x channels regulate neuronal excitability and responsiveness to synaptic input patterns. K_Ca 2.x channels inhibit excitatory postsynaptic potentials (EPSPs) in neuronal dendrites and contribute to the medium afterhyperpolarization (mAHP) that follows the action potential bursts. Multiple brain regions, including the hippocampus, express the K_Ca 2.2 channel encoded by the KCNN2 gene on chromosome 5. Of particular interest, rat cerebellar Purkinje cells express K_Ca 2.2 channels, which are crucial for various cellular processes during development and maturation. Patients with a loss-of-function of KCNN2 mutations typically exhibit extrapyramidal symptoms, cerebellar ataxia, motor and language developmental delays, and intellectual disabilities. Studies have revealed that autosomal dominant neurodevelopmental movement disorders resembling rodent symptoms are caused by heterozygous loss-of-function mutations, which are most likely to induce KCNN2 haploinsufficiency. The K_Ca 2.2 channel is a promising drug target for spinocerebellar ataxias (SCAs). SCAs exhibit the dysregulation of firing in cerebellar Purkinje cells which is one of the first signs of pathology. Thus, selective K_Ca 2.2 modulators are promising potential therapeutics for SCAs.