Sodium-Activated Potassium Channels and Their Role in Neuronal Excitability
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The sodium-activated potassium (K Na ) channel subfamily is comprised of two member subunits termed Slack and Slick (encoded by the KCNT1 and KCNT2 genes, respectively), which homo- and/or hetero-tetramerize to form functional channels that conduct large, outward rectifying K + currents ( I KNa ). Distinct from other large potassium channel subtypes, K Na channels are activated by increases in intracellular sodium and are only weakly sensitive to membrane voltage. Given their wide expression throughout the nervous system, several functional examples of elevated [Na + ]i leading to IK Na have been identified, such as subsequent to a train of action potentials or following activation of excitatory neurotransmitter receptors such as AMPA receptors. Loss of I KNa by reduced channel conductance or membrane density profoundly alters the ability of neurons to adapt to maintained excitation, resulting in repetitive action potential firing, termed as membrane hyperexcitability. Although nascent, work on the molecular mechanisms underlying the channels’ significant role in neuronal excitability has implicated their uniquely large intracellular C-terminus as a regulatory hub for cytoplasmic protein interactions. Slack K Na channels are directly and/or indirectly regulated by several such cytoplasmic proteins, including the second messenger cAMP, protein kinase enzymes such as PKC and ion channel TMEM16C. We have added to the existing body of work on Slack channel regulation with the description of two novel intracellular protein interactions that profoundly impact firing frequency and membrane excitability in the sensory neurons of the dorsal root ganglion, thereby having significant effects on nociceptive sensitization. Evidence of K Na channels’ critical role in neuronal membrane excitability is bolstered by recent identification of several human mutations in Slack channels that cause severe defects in learning and development, suggesting that Slack channels are central to neuronal plasticity and intellectual function. The recent identification of about 13 KCNT1 mutations in human patients of various forms of infantile epilepsy has made the Slack channel into a promising clinical target. We have characterized the first identified human mutation in the KCNT2 gene in an epilepsy patient and established it to be pathogenic, but via a mechanism of altered selectivity that is distinct from the KCNT1 mutations reported thus far. Together, the findings described here substantiate the critical role of K Na channels in neuronal excitability, establish novel cellular mechanisms underlying physiological and pathological K Na channel function and identify promising new targets for the study of peripheral sensitization and nociception.