TMEM16C facilitates sodium-activated potassium currents in rat primary sensory neurons and regulates pain processing

TMEM16C belongs to the TMEM16 family, which includes the Ca(2+)-activated Cl(–) channels (CaCCs) TMEM16A and TMEM16B and a small conductance Ca(2+)-activated, non-selective cation channel (SCAN), TMEM16F. Here we report that in rat dorsal root ganglia (DRG) TMEM16C is expressed mainly in the IB4 positive, non-peptidergic nociceptors that also express the sodium-activated potassium (KNa) channel Slack. Together these channel proteins promote KNa channel activity and dampen neuronal excitability. DRG from TMEM16C knock out rats have reduced Slack expression, broadened action potential and increased excitability. Moreover, the TMEM16C knock out rats as well as rats with Slack knockdown via intrathecal injection of siRNA exhibit increased thermal and mechanical sensitivity. Experiments involving heterologous expression in HEK293 cells further show that TMEM16C modulates the single channel activity of Slack channels and increases its sodium sensitivity. Our study thus reveals that TMEM16C enhances KNa channel activity in DRG neurons and regulate the processing of pain messages.