1.A.1.2.11
Voltage-gated K⁺ channel, Shab-related, K_v2.1 or KCNB1 (858aas) The crystal structure is known (Long et al., 2007). Rat K_v2.1 and K_v2.2 (long) are colocalized in the somata and proximal dendrites of cortical pyramidal neurons and are capable of forming functional heteromeric delayed rectifier channels. The delayed rectifer currents, which regulate action potential firing, are encoded by heteromeric K_v2 channels in cortical neurons (Kihira et al., 2010). Phosphorylation by AMP-activated protein kinase regulates membrane excitability (Ikematsu et al., 2011). Functional interactions between residues in the S1, S4, and S5 domains of Kv2.1 have been identified (Bocksteins et al., 2011).  Missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminus cause neurodevelopmental disorders, sometimes with seizures (de Kovel et al. 2017).  Kv2.1 channels consist of two types of alpha-subunits: (1) electrically-active Kcnb1 alpha-subunits and (2) silent or modulatory alpha-subunits plus beta-subunits that, similar to silent alpha-subunits, regulate electrically-active subunits (Jędrychowska and Korzh 2019). It plays a role  in neurodevelopmental disorders, such as epileptic encephalopathy. The N- and C-terminal domains of the alpha-subunits interact to form the cytoplasmic subunit of hetero-tetrameric potassium channels. Kcnb1-containing channels are involved in brain development and reproduction. Modification of Kv2.1 K⁺ currents is mediated by the silent Kv10 subunits (Vega-Saenz de Miera 2004). The clinical expression of KCNB1 encephalopathy is variable (Púa-Torrejón et al. 2021). Variants of KCNB1, located in the S1 segment, may be associated with a milder outcome of seizures (Hiraide et al. 2022). Altered neurological and neurobehavioral phenotypes have been observed in a mouse model of the recurrent KCNB1 -p.R306C voltage-sensor variant (Kang et al. 2023). A point mutation (M340I) in K_V2.1 may cause severe and treatment-resistant obsessive-compulsive disorder (trOCD) (Chen et al. 2023; Ji et al. 2023). It may play a role in Parkinson's Disease (Zhou et al. 2023).  An autism-associated KCNB1 mutation dramatically slows Kv2.1 potassium channel activation, deactivation and inactivation (Manville RW et al., 2024 [not yet in PubMed]).