The Slack Potassium Ion channel as a Therapeutic Target for Fragile X Syndrome
A paper on this work has been published in Journal of Neuroscience on 2010 August 4: Fragile X mental retardation protein is required for rapid experience-dependent regulation of the potassium channel Kv3.1b
by Leonard Kaczmarek, PhD and Jack Kronengold, PhD
Our laboratory has investigated how the excitability of neurons becomes modified in the absence of the FMRP protein. We have found that the levels of two potassium channels, termed Slack and Kv3.1 are altered in mice that lack this protein. We have made significant progress in identifying novel pharmacological activators of the Slack potassium channel for potential therapeutic intervention in FXS individuals.
The Slack potassium channel is widely expressed in the brain. Using neurons of the central auditory system, our laboratory has demonstrated that Slack is required for accurate timing of action potentials in response to synaptic stimuli. This channel is activated by the FMRP protein through a direct association of FMRP with the cytoplasmic domain of the channel itself. We have shown that levels of the Slack potassium current are reduced by about 50% in neurons of FMR1-/- mice. Treatment of neurons with pharmacological activators of Slack would be expected to restore levels of this current back to levels found in wild type animals. Using a combination of electrophysiological and biochemical assays, we have now identified five compounds that are effective activators of Slack channels and are now testing their specificity for this class of channels.
In addition, we have recently published work (see below) that has identified another potassium channel, Kv3.1, that is altered by loss of FMRP. The physiological role of this channel is to allow specific types of neurons to fire at very high rates. We have found that Kv3.1 mRNA is a binding partner for FMRP, and that in FMR1-/- mice, levels of this channel are elevated. Moreover, in the central auditory system Kv3.1 is normally expressed in an orderly tonotopic gradient, such that neurons responding to the highest frequency sounds have the highest levels of Kv3.1 channel. This orderly gradient is abolished in the absence of FMRP, causing all these neurons to have uniformly high levels of this channel. This finding suggests that auditory neurons are likely to be hyperexcitable in FXS individuals. In collaboration with a pharmaceutical company, we are therefore now investigating the actions of activators and inhibitors of the Kv3.1 potassium channel.