The transcription factor Smad-interacting protein 1 controls pain sensitivity via modulation of DRG neuron excitability

The perception of pain is initiated by the transduction of noxious stimuli through specialized ion channels and receptors expressed by primary nociceptive neurons. The molecular mechanisms that orchestrate the expression and function of ion channels relevant for pain processing are poorly understood. We demonstrate here a central role of the transcription factor Smad-interacting protein 1 (Sip1/Zfhx1b/Zeb2), a 2-handed zinc finger DNA-binding protein with essential functions in neural crest and forebrain development, in controlling nociceptive neuron excitability and pain sensitivity. Mutant mice lacking 1 Zfhx1b allele displayed decreased thermal pain responses, whereas mechanical pain was unaffected. In parallel, repetitive firing of capsaicin/heat-sensitive nociceptive DRG neurons was markedly impaired. Analysis of the voltage-gated currents underlying repetitive firing revealed a significant increase in persistent sodium currents and a reduction in delayed rectifier potassium currents. Modeling experiments in conjunction with experimental results suggest that these changes cause a depolarization-induced block of action potential propagation past the DRG axon T-junction. These data suggest that Sip1 controls the transduction properties of heat-sensitive primary sensory neurons and thus thermal pain sensitivity in a novel manner via coordinated changes in DRG-neuron voltage-gated ion channels.