Membrane potential-regulated transcription of the resting K+ conductance TASK-3 via the calcineurin pathway

The 2P domain K+ channel TASK-3 is highly expressed in cerebellar granule neurons where it has been proposed to underlie the K+ leak conductance, IKso. In a previous work we showed that expression of TASK-3 increases in cerebellar granule neurons as they mature in culture. Here we show that within the cerebellum, levels of TASK-3 mRNA increase as granule neurons migrate to their adult positions and receive excitatory mossy fiber input. To understand the mechanism of this increase in TASK-3 expression we used an in vitro model culturing the neurons in either depolarizing conditions mimicking neuronal activity (25K, 25 mM KCl) or in conditions which approach deafferentation (5K, 5 mM KCl). An important increase in TASK-3 mRNA is uniquely observed in 25K and is specific since other background K+ channel levels remain unchanged or decrease. The rise in TASK-3 mRNA leads to an increase in TASK-3 protein and the IKso conductance resulting in hyperpolarization. Blocking L-type calcium channels or their downstream effector calcineurin, abrogates TASK-3 expression and IKso, leading to hyperexcitability. This is the first study demonstrating that depolarization-induced Ca2+ entry can directly regulate cellular excitability by dynamically regulating the transcription of a resting K+ conductance. The appearance of this conductance may play an important role in the transition of depolarized immature neurons to their mature hyperpolarized state during neuronal development.