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KCNB1, also known as Kv2.1, is expressed in the central nervous system, pulmonary arteries, pancreas, auditory outer hair cells, heart, stem cells and retina. As in other voltage-gated K+ channels, KCNB1 spatial and temporal expressions are both developmentally regulated.KCNB1 shows a large number of unusual phosphorylation consensus sites. Accordingly, the channel is a substrate for protein kinases of different families and is constitutively phosphorylated in native cells. KCNB1 can also be overacylated and acetylated in the nervous system and pancreas.
KCNB1 is highly expressed in the neurons throughout the brain and forms the principal delayed rectifier current of many neuron types. KCNB1 plays important roles in regulating neuronal excitability, contributing to action potential repolarization and dynamic modulation of neuronal activity. In electrically quiescent neurons, KCNB1 is mostly localized in microdomains in the membranes of dendrites and cell bodies where it is constitutively phosphorylated and poorly conducting. At the beginning of neuronal activity, a series of cellular events are initiated that lead to de-phosphorylation of the channel. Activity-dependent phosphorylation/de-phosphorylation of KCNB1is partly mediated by cyclin-dependent kinase 5 and the phosphatase calcineurin. The latter is activated by calcium influx driven by the electrical activity of neurons. In addition to its electrical roles in neurons, KCNB1 plays a less understood structural role in neurons. KCNB1 channels form large clusters on the cell body, proximal dendrites, and axon initial segments of neurons that represent plasma membrane–ER junctions. The majority of these clustered channels are reported to be non-conducting. The presence of KCNB1 drives recruitment of other proteins to these clusters, indicating that subcellular localization of KCNB1 could have neurophysiological consequences beyond electrical signaling. Genetic defects in KCNB1 lead to neurological consequences. Mice lacking KCNB1 are strikingly hyperactive, defective in spatial learning, hypersensitive to convulsants, and exhibit accelerated seizure progression.
Loss-of-function mutations in KCNB1 have been linked to early infantile epileptic encephalopathy and KCNB1 knockout in mice causes hippocampal hyperexcitability and seizures. Additionally, during conditions of oxidative stress, reactive oxygen species (ROS) act to modify KCNB1 channels in a manner that they become cytotoxic. For example, in mouse model of traumatic brain injury (TBI), oxidized KCNB1 channels contribute to tissue damage and consequent behavioral impairment. Oxidized KCNB1 channels are also present in the brains of aging mice and in larger amounts in the brain of 3x-Tg-AD mouse model of Alzheimer’s disease, where they promote hyperexcitability and presumably apoptosis.
Pharmacological inhibition of KCNB1 current may represent a valid approach to preventing apoptosis. Some reports have shown that carbon monoxide (CO) can provide neuronal protection against an increase in KCNB1 current via regulating ROS and protein kinase G activity, the anti-apoptotic effect of CO may also be partially responsible for the etiology of cancer, as many oncogenic cells constitutively express heme oxygenase-1 (HO-1), which generates CO as a byproduct of its catalytic activity. Chronic viruses, which establish a state of persistent infection by rendering infected cells resistant to apoptosis, also appear to exploit inhibition of KCNB1 current. In human hepatocytes infected with hepatitis C virus (HCV), oxidative insults fail to initiate apoptosis because the HCV NS5A protein inhibits phosphorylation of KCNB1 by p38 MAPK and thus suppresses the current surge. Furthermore, a neuronal NS5A isoform from HCV genotype 1b, NS5A1b, protects rat neurons against apoptosis by inhibiting KCNB1. Furthermore, the transient accumulation of KCNB1 oligomers is associated with activation of c-Src and JNK kinases coupled to a steady increase in the levels of free radicals. Thus, oligomer-induced activation of a “death pathway” appears to trigger the initial pro-apoptotic stimulus. As apoptosis progresses and ROS levels increase in the cell, the surge of KCNB1 current follows to further execute the apoptotic program (Figure 1).
Figure 1. A two-step model for the pro-apoptotic actions of KCNB1.