Abstract
The sodium-activated potassium KNa channels Slack and Slick are encoded by KCNT1 and KCNT2, respectively. These channels are found in neurons throughout the brain, and are responsible for a delayed outward current termed IKNa. These currents integrate into shaping neuronal excitability, as well as adaptation in response to maintained stimulation. Abnormal Slack channel activity may play a role in Fragile X syndrome, the most common cause for intellectual disability and inherited autism. Slack channels interact directly with the fragile X mental retardation protein (FMRP) and IKNa is reduced in animal models of Fragile X syndrome that lack FMRP. Human Slack mutations that alter channel activity can also lead to intellectual disability, as has been found for several childhood epileptic disorders. Ongoing research is elucidating the relationship between mutant Slack channel activity, development of early onset epilepsies and intellectual impairment. This review describes the emerging role of Slack channels in intellectual disability, coupled with an overview of the physiological role of neuronal IKNa currents.
Highlights
An influx of sodium ions through sodium channels or neurotransmitter receptors triggers a sodium-sensitive potassium current (IKNa), which is found in a diverse range of neuronal cell types
These new findings strengthened an earlier connection between Slack channels and Fragile X syndrome (FXS); Slack channels interact with fragile X mental retardation protein (FMRP) (Fragile X Mental Retardation protein; Brown et al, 2010), which is absent in FXS patients
These new findings collectively suggest that dysregulation of an acute modulation of neuronal excitability and transmission by FMRP may contribute to the intellectual disability associated with FXS
Summary
An influx of sodium ions through sodium channels or neurotransmitter receptors triggers a sodium-sensitive potassium current (IKNa), which is found in a diverse range of neuronal cell types. FXS as a condition is associated with an increased incidence of childhood seizures, and is the most commonly inherited form of intellectual disability and autism These observations suggest that Slack channels are developmentally important modulators of cell plasticity underlying normal cognitive development. Like the Kv channels, Slack subunits have six hydrophobic, transmembrane segments (S1–S6) along with a pore-lining loop that is found between S5 and S6 (Figure 1) These subunits assemble as tetramers to form a functional channel that is voltage-dependent (Joiner et al, 1998). Another distinguishing feature of Slack channels is their very large cytoplasmic C-terminal domain, which is over 900 amino acids in length (Joiner et al, 1998), making Slack channels the Frontiers in Cellular Neuroscience www.frontiersin.org
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