1.A.1.2.10
Voltage-gated K⁺ channel, chain A, Shaker-related, K_v1.2 or KCNA2 (Crystal structure known, Long et al., 2007; Chen et al. 2010). It functions with the auxiliary subunit, Ivβ1.2; 8.A.5.1.1) (Peters et al. 2009).  Delemotte et al. (2010) described the effects of sensor domain mutations on molecular dynamics of K_v1.2.  The Sigma 1 receptor (Q99720; Sigma non-opioid intracellular receptor 1) interacts with K_v1.2 to shape neuronal and behavioral responses to cocaine (Kourrich et al. 2013).  Amino acid substitutions cause Shaker to become heat-sensing (opens with increasing temperature as for TrpV1) or cold-sensing (opens with decreasing temperature as for TrpM8) (Chowdhury et al. 2014).  The Shaker Kv channel was truncated after the 4th transmembrane helix S4 (Shaker-iVSD) which showed altered gating kinetics and formed a cation-selective ion channel with a strong preference for protons (Zhao and Blunck 2016).  Direct axon-to-myelin linkage by abundant K_V1/Cx29 (TC# 1.A.24.1.12) channel interactions in rodent axons supports the idea of an electrically active role for myelin in increasing both the saltatory conduction velocity and the maximal propagation frequency in mammalian myelinated axons (Rash et al. 2016). A cryoEM structure (3 - 4 Å resolution; paddle chimeric channel; closed form) in nanodiscs has been determined (Matthies et al. 2018). Possible gating mechanisms have been discussed (Kariev and Green 2018; Infield et al. 2018). Pathogenic variants in KCNA2, encoding the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction (Döring et al. 2021). In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. Biophysical properties of a delayed rectifier K⁺ current can contribute to its role in generating spontaneous myogenic activity (Hu et al. 2021). The local curvature of cellular membranes acts as a driving force for the targeting of membrane-associated proteins to specific membrane domains, as well as a sorting mechanism for transmembrane proteins, as demonstrated for the chimeric channel, Kv1.2/2.1; KvChim induces strong positive membrane curvature (Kluge et al. 2022). 2-Aminoethoxydiphenyl borate (2-APB) has inhibitory effects on three K_V1 channels, Kv1.2, Kv1.3 and Kv1.4 (Zhao et al. 2023). Voltage-gated K⁺ channels have two distinct gates that regulate ion flux: the activation gate (A-gate) formed by the bundle crossing of the S6 TMSs and the slow inactivation gate in the selectivity filter. These two gates are bidirectionally coupled. Szanto et al. 2023 suggested that the coupling between the A-gate and the slow inactivation gate is mediated by rearrangements in the S6 segment. S6 rearrangements are consistent with a rigid rod-like rotation of S6 around its longitudinal axis upon inactivation.  Regulators of K_V1.2 include the neutral amino acid transporter Slc7a5 which causes a dramatic hyperpolarizing shift of channel activation. In contrast, the transmembrane lectin LMAN2 is a regulator that has the opposite effect on gating: large depolarizing voltages are required to activate K_V1.2 channels co-expressed with LMAN2.  Slc7a5 and LMAN2 compete for interaction with the K_V1.2 voltage sensor (Das et al. 2024).  CryoEM structures of Kv1.2 potassium channels, in conducting and non-conducting states, have appeared (Wu et al. 2025).