Summary Subthreshold-activating A-type K+ currents are essential for the proper functioning of the brain where they act to delay excitation and regulate firing frequency. In CA1 hippocampal pyramidal neuron dendrites, the density of A-type K+ current increases with distance from the soma, playing an important role in synaptic integration and plasticity. The mechanism underlying this gradient has, however, remained elusive. Here, dendritic recordings from mice lacking the Kv4 transmembrane auxiliary subunit DPP6 revealed that this protein is critical for generating the A-current gradient. Loss of DPP6 led to a decrease in A-type current, specifically in distal dendrites. Decreased current density was accompanied by a depolarizing shift in the voltage-dependence of channel activation. Together these changes resulted in hyperexcitable dendrites with enhanced dendritic AP back-propagation, calcium electrogenesis and induction of synaptic long-term potentiation. Despite enhanced dendritic excitability, firing behavior evoked by somatic current injection was mainly unaffected in DPP6-KO recordings, indicating compartmentalized regulation of neuronal excitability.

Key points• AmmTX3, a member of the α-KTX15 family of scorpion toxins, efficiently and specifically blocks the subthreshold-operating A-type K + current in cerebellar granule neurons from wild-type mice but not in neurons from mice lacking the Kv4 channel-associated protein DPP6.• In heterologous cells high-affinity blockade of Kv4.2 and Kv4.3 channels by AmmTX3 requires the presence of the associated proteins DPP6 and DPP10.• These results validate AmmTX3 as a specific blocker of Kv4 channels in CNS neurons and explain the discrepancy between previous observations in neurons and heterologous cells.• They contribute a powerful tool to investigate the physiological role of A-type K + currents, believed to be important in dendritic integration and plasticity and to be involved in a number of diseases.• Our results demonstrate that, in addition to changing the kinetics and voltage dependence of Kv4 channel complexes, DDP-like Kv4-associated proteins also affect their pharmacological profile.Abstract K + channels containing Kv4.2 and Kv4.3 pore-forming subunits mediate most of the subthreshold-operating somatodendritic A-type K + current in CNS neurons. These channels are believed to be important in regulating the frequency of repetitive firing, the backpropagation of action potential into dendrites, and dendritic integration and plasticity. Moreover, they have been implicated in several diseases from pain to epilepsy and autism spectrum disorders. The lack of toxins that specifically and efficiently block these channels has hampered studies aimed at confirming their functional role and their involvement in disease. AmmTX3 and other related members of the α-KTX15 family of scorpion toxins have been shown to block the A-type K + current in cultured neurons, but their specificity has been questioned because the toxins do not efficiently block the currents mediated by Kv4.2 or Kv4.3 subunits expressed in heterologous cells. Here we show that the high-affinity blockade of Kv4.2 and Kv4.3 channels by AmmTX3 depends on the presence of the auxiliary subunits DPP6 and DPP10. These proteins are thought to be components of the Kv4 channel complex in neurons and to be important for channel expression in dendrites. These studies validate the use of AmmTX3 as a blocker of the Kv4-mediated A-type K + current in neurons.

No abstract