With a $282,000 funding from FRAXA Research Foundation, Dr. Leonard Kaczmarek and colleagues explored association of Slack channels with the Fragile X protein (FMRP).
Individuals with Fragile X syndrome commonly report an increased awareness of environmental sounds, abnormal loudness perception, and difficulty in filtering or “hearing out” the important auditory information in background noise. This manifests itself as paying too much attention to stimuli that most people ignore, or not responding to the most important messages that are confronting the person. These symptoms interfere with attention, learning, language development and social interactions and are likely due to changes in synaptic connections in sensory circuits; the breakdown of the normal flow of information along pathways in the brain.
The integrity of neuronal encoding and processing of sensory input is dependent on a precise complement of ion channels that shape neuronal action potentials and determine their firing patterns and frequency of firing. Specifically, Na+ – activated potassium channels (termed KNa channels) are critical for this function. We have found that the Slack KNa channel directly binds the Fragile X protein (FMRP), resulting in a several-fold activation of Slack channel activity.
The association of Slack channels with FMRP suggests that pharmacological manipulations of channel activity could prove to be a novel therapy for Fragile X syndrome. In particular, FMRP knockout mice lack a physiological activator of Slack channel (FMRP itself) and expression of a C-terminal Slack isoform is completely abolished in fmrl-/- mice, leading to significantly reduced Slack currents. Thus some of the neuronal abnormalities associated with Fragile X may result from the effect of altered K currents on neuronal excitability and timing. Moreover our findings suggest that the interaction of Slack channels with FMRP could regulate rates of translation of mRNAs bound to FMRP.
Our laboratory is developing a range of compounds that can activate Slack channels. We plan to determine whether these compounds enhance Slack channel activity and restore normal firing patterns in neurons from fmrl-/- mice. If we find potent and selective compounds, this will provide a strong impetus for the evaluation of Slack activators as novel therapeutic agents that could act either independently or in concert with agents that act at group1 metabotropic glutamate receptors, which have been found to regulate Slack channels.
Results published in Nature Neurosci. 2010 Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack