TMEM16C facilitates Na+-activated K+ currents in rat sensory neurons and regulates pain processing

TMEM16C belongs to the TMEM16 family, which includes the Ca2+-activated Cl- channels TMEM16A and TMEM16B and a small-conductance, Ca2+-activated, nonselective cation channel (SCAN), TMEM16F. We found that in rat dorsal root ganglia (DRG) TMEM16C was expressed mainly in the IB4-positive, non-peptidergic nociceptors that also express the sodium-activated potassium (K-Na) channel Slack. Together these channel proteins promote K-Na channel activity and dampen neuronal excitability. DRG from TMEM16C knockout rats had diminished Slack expression, broadened action potentials and increased excitability. Moreover, the TMEM16C knockout rats, as well as rats with Slack knockdown by intrathecal injection of short interfering RNA, exhibited increased thermal and mechanical sensitivity. Experiments involving heterologous expression in HEK293 cells further showed that TMEM16C modulated the single-channel activity of Slack channels and increased its sodium sensitivity. Our study thus reveals that TMEM16C enhances K-Na channel activity in DRG neurons and regulates the processing of pain messages.