Terbinafine is a novel and selective activator of the two-pore domain potassium channel TASK3

Two-pore domain potassium channels (K2Ps) are characterized by their four transmembrane domain and two-pore topology. They carry background (or leak) potassium current in a variety of cell types. Despite a number of important roles there is currently a lack of pharmacological tools with which to further probe K2P function. We have developed a cell-based thallium flux assay, using baculovirus delivered TASK3 (TWIK-related acid-sensitive K+ channel 3, KCNK9, K2P9.1) with the aim of identifying novel, selective TASK3 activators. After screening a library of 1000 compounds, including drug-like and FDA approved molecules, we identified Terbinafine as an activator of TASK3. In a thallium flux assay a pEC50 of 6.2 ( ±0.12) was observed. When Terbinafine was screened against TASK2, TREK2, THIK1, TWIK1 and TRESK no activation was observed in thallium flux assays. Several analogues of Terbinafine were also purchased and structure activity relationships examined. To confirm Terbinafine's activation of TASK3 whole cell patch clamp electrophysiology was carried out and clear potentiation observed in both the wild type channel and the pathophysiological, Birk-Barel syndrome associated, G236R TASK3 mutant. No activity at TASK1 was observed in electrophysiology studies. In conclusion, we have identified the first selective activator of the two-pore domain potassium channel TASK3

Examining the influence of pyramidal neuron progenitor type on cortical subnetworks

The precise synaptic connectivity between cortical neurons determines how infor- mation is integrated and processed by the mammalian cortex. In somatosensory cortex, for example, excitatory and inhibitory cell types form fine-scale synaptic circuits, which integrate feedforward sensory information with feedback contextual information. The principles by which excitatory and inhibitory neurons are arranged into functional circuits, however, remain unknown. Recent evidence suggests that an excitatory cortical neuron’s synaptic connectivity and functional properties can reflect the progenitor type from which the neuron is derived during embryonic de- velopment. By combining longitudinal in utero lineage labelling techniques with patch-clamp electrophysiology in mature cortex, I test whether progenitor type in- fluences the local synaptic inhibition and cortical feedback received by excitatory pyramidal neurons in layer 2/3 (L2/3) of mouse somatosensory cortex. Firstly, I find that progenitor type predicts a L2/3 pyramidal neuron’s inhibitory synaptic activity in vivo. Secondly, I find that L2/3 pyramidal neuron progenitor type is not associated with different amounts of inhibition from interneuron subtypes. Rather, progenitor type defines how much inhibitory synaptic input a L2/3 pyramidal neuron shares with its neighbours. Consistent with this, interneurons target neighbouring pyramidal neurons based on the post-synaptic neuron’s progenitor type. Finally, I find that progenitor type predicts the degree to which L2/3 pyramidal neurons are recruited by long-range excitatory feedback from primary motor cortex. These ob- servations reveal new significance for progenitor diversity and identify ontogenetic mechanisms underlying fine-scale inhibitory subnetworks and long-range feedback circuits in cortex