Neuronal potassium channel activity triggers initiation of mRNA translation through binding of translation regulators

Neuronal activity stimulates mRNA translation crucial for learning and development, but the mechanism linking translation to neuronal activity is not understood. In humans, learning and memory are severely disrupted by mutations in the potassium channel Slack (KCNT1, Slo2.2). We find that pharmacological stimulation of this channel and a constitutively active Slack mutation stimulate mRNA translation of a reporter for β-actin mRNA in cell lines and increases the synthesis of β-actin in the neurites of cortical neurons. Moreover, channel activation promotes the binding of two key mRNA translation regulators, FMRP (fragile X mental retardation protein) and CYFIP1 (cytoplasmic FMR1-interacting protein 1), to the channel itself, releasing both from eIF4E (eukaryotic initiation factor 4E), where they normally inhibit initiation of translation. This interaction provides a molecular mechanism for Slack activity-dependent regulation of translation and suggests that the effects of Slack mutations on this process may explain the severe intellectual disabilities associated with these mutations.