TRPM4 mediates a subthreshold membrane potential oscillation in respiratory chemoreceptor neurons that drives pacemaker firing and breathing

Cell Rep. 2021 Feb 2;34(5):108714. doi: 10.1016/j.celrep.2021.108714.


Brainstem networks that control regular tidal breathing depend on excitatory drive, including from tonically active, CO2/H+-sensitive neurons of the retrotrapezoid nucleus (RTN). Here, we examine intrinsic ionic mechanisms underlying the metronomic firing activity characteristic of RTN neurons. In mouse brainstem slices, large-amplitude membrane potential oscillations are evident in synaptically isolated RTN neurons after blocking action potentials. The voltage-dependent oscillations are abolished by sodium replacement; blocking calcium channels (primarily L-type); chelating intracellular Ca2+; and inhibiting TRPM4, a Ca2+-dependent cationic channel. Likewise, oscillation voltage waveform currents are sensitive to calcium and TRPM4 channel blockers. Extracellular acidification and serotonin (5-HT) evoke membrane depolarization that augments TRPM4-dependent oscillatory activity and action potential discharge. Finally, inhibition of TRPM4 channels in the RTN of anesthetized mice reduces central respiratory output. These data implicate TRPM4 in a subthreshold oscillation that supports the pacemaker-like firing of RTN neurons required for basal, CO2-stimulated, and state-dependent breathing.

Keywords: I(CaN); RTN; intrinsic excitability; retrotrapezoid nucleus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemoreceptor Cells / metabolism*
  • Humans
  • Membrane Potentials / genetics*
  • Mice
  • Neurons / metabolism*
  • Respiration / genetics*
  • TRPM Cation Channels / metabolism*


  • TRPM Cation Channels
  • TRPM4 protein, mouse