Emerging role of the KCNT1 Slack channel in intellectual disability

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 I KNa. 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 I KNa 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 I KNa currents.

Keywords: Fragile X syndrome; KCNT1; Slack; epilepsy; intellectual disability.

FIGURE 1

A schematic diagram of Slack subunit topography. Slack subunits have six transmembrane domains. These hydrophobic transmembrane segments are labeled as S1–S6, with the pore region between S5 and S6 indicated with the letter P. Four of these subunits assemble into a functional channel. Both the N- and C-terminal ends are cytosolic in Slack, with C-terminus being one of the longest found among all potassium channels. The C-terminus contains two RCK (regulators of K⁺ conductance) domains that stack on top of each other and form a gating ring underneath the channel opening pore. Gray circles represent the general locations where human mutations have been found. A total of thirteen distinct mutations have been found to date, and these mutations are discussed further in the text.

FIGURE 2

Co-diagnosis rates among FXS, ASD and epilepsy patients. This diagram shows the prevalence of co-diagnosis in fragile x syndrome (FXS), autism spectrum disorder (ASD) and epilepsy patients, as reported in Refs. (Musumeci et al., 1999; Muhle et al., 2004; Abrahams and Geschwind, 2008; Amiet et al., 2008; Bailey et al., 2008; Hernandez et al., 2009; Yasuhara, 2010; Jokiranta et al., 2014).