K2P Channels Regulate Presynaptic Organisation through a Membrane Potential-Independent Mechanism

Neuronal ion channels have well-established effects on synaptic plasticity, in many cases by influencing pathways that depend on membrane excitability. Here we find that a C. elegans two-pore domain potassium (K2P) channel, TWK-40, regulates presynaptic organisation through a membrane potential-independent mechanism. Instead, this mechanism depends on TWK-40's effects on intracellular potassium levels. Loss-of-function mutations in twk-40 lead to excessive presynaptic protein accumulation, while gain-of-function mutations lead to depleted presynaptic components and cause synaptic transmission deficits. These changes in presynaptic protein abundance are phenocopied by transporter mutations predicted to alter intracellular potassium homeostasis in the same direction as TWK-40 mutations, but not by sodium channel mutations that mimic its effects on membrane excitability. This indicates that cytoplasmic potassium promotes presynaptic assembly. This process depends on pyruvate kinase PYK-1, a potassium-sensitive enzyme, and three transcription factors. These findings establish a new pathway linking neuronal potassium homeostasis to the control of presynaptic organisation and synaptic function.