Abstract
Dipeptidyl Peptidase-like Protein 6 (DPP6) is widely expressed in the brain where it co-assembles with Kv4 channels and KChIP auxiliary subunits to regulate the amplitude and functional properties of the somatodendritic A-current, ISA. Here we show that in cerebellar granule (CG) cells DPP6 also regulates resting membrane potential and input resistance by increasing the amplitude of the IK(SO) resting membrane current. Pharmacological analysis shows that DPP6 acts through the control of a channel with properties matching the K2P channel TASK-3. Heterologous expression and co-immunoprecipitation shows that DPP6 co-expression with TASK-3 results in the formation of a protein complex that enhances resting membrane potassium conductance. The co-regulation of resting and voltage-gated channels by DPP6 produces coordinate shifts in resting membrane potential and A-current gating that optimize the sensitivity of ISA inactivation gating to subthreshold fluctuations in resting membrane potential.
Highlights
The cerebellum plays a critical role in motor learning and cognitive function by adjusting neuronal firing patterns to match desired behavioral outcomes [1]
Application of a lentiviral vector expressing RNAi targeting a mouse Dipeptidyl peptidase-like protein 6 (DPP6) core sequence dramatically increases the excitability of mouse Cerebellar granule (CG) cells
Calmodulin plays an integral role in many channels and enzymes, Na+ channel auxiliary subunits have been identified as important components of voltage-gated potassium channels, KChIPs have been shown to regulate the function of both voltagegated calcium channels and potassium channels as well as regulate gene transcription, and KCNE1-5 can regulate both KCNQ channels as well as HERG channels and likely other potassium channels [42,43,44,45,46,47]
Summary
The cerebellum plays a critical role in motor learning and cognitive function by adjusting neuronal firing patterns to match desired behavioral outcomes [1]. Factors regulating CG cell firing are critically important for the function of the cerebellum since more than 150,000 different CG cell inputs converge onto a single Purkinje neuron dendrite [2]. Precise regulation of both resting and voltage-gated channels is required for CG cells to process input signals and generate appropriate output firing. ‘‘window’’ currents from A-type channels can contribute to the regulation of resting input resistance [7], other potential mechanisms exist by which DPP6 expression could affect excitability. In CG cells, IK(SO), a muscarine sensitive resting membrane potassium current plays an important role in regulating excitability [8]. Previous work has suggested that IK(SO) is most likely formed by K2P type channels, and may be an amalgamation of several different K2P channel types [9,10,11,12]
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