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

Abstract

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.

Keywords: KCa2.2 channels; Purkinje cells; cerebellar ataxia; medium afterhyperpolarization; spinocerebellar ataxias.

Figure 1.1. Subfamilies of potassium channels.

Subfamilies of potassium channels include two transmembrane segments (two TM; Kir), four TM (two-pore domain), six TM (voltage-gated, K_Ca2.x, and K_Ca3.1), and seven TM (BK). K_Ca2.x family is subdivided into K_Ca2.1, K_Ca2.2, and K_Ca2.3 [5], [9].

Figure 1.2.. Pore-forming unit and regulatory unit of K_Ca2.2 channels.

Channels are regulated at their N and C termini by binding protein phosphatases and kinases[38].

Figure 1.3.. K_Ca2.2 channels roles in medium after-hyperpolarization.

Upon neuronal activity, voltage-gated & Ca²⁺-activated K⁺ channels are engaged during repolarization (K_V) and during after-hyperpolarization to provide feedback inhibition at nerve terminals. They do so by restricting action potential duration and thus neurotransmitter release[46].

Figure 1.4.. A schematic illustrating the localization and regulatory pathways involving the K_Ca2.2 channel in neurons [30].

The K_Ca2.2 channel couplesg to Ca²⁺ sources on a physical and functional level. This figure illustrates the simplified graphical view of Ca²⁺ sources and K_Ca2.2 channels gating upon binding with Ca²⁺ [27].

Figure 1.5.. A schematic representation of one K_Ca2.2 channel subunit.

The pathogenic LOF mutations are shown as red circles [22,75].

Figure 1.6.. Prevalence of SCAs based on geographical location [–87].